Prof. Jonathan L. Sessler
Prof. JunLong Zhang
Prof. Justin Wilson
Prof. Taotao Zou
Prof. Maria V. Babak
Prof. Jim A Thomas
Prof. Caixia Yin
Prof. Xiaoyong Wang
Prof. Nils Metzler-Nolte
Prof. HongKe Liu
Prof. Luigi Messori
Prof. Jose Ruiz
Prof. Thomas J. Meade
Prof. Jong Seung Kim
Prof. Samuel G. Awuah
Prof. Cai-Ping Tan
Prof. Kenneth Kam-Wing Lo
Prof. Yangzhong Liu
Prof. Christian G. Hartinger
Prof. Zhen-Feng Chen
Prof. Gilles Gasser
Prof. Hui Chao
Prof. Walter Berger
Prof. Fuyi Wang
Day 1 (Aug 26, 2022)
Jonathan L. Sessler
Professor
The University of Texas at Austin
Texas-inspired Drug Discovery Efforts
Abstract
This lecture will present the development of expanded porphyrins as
potential
drug leads. The presentation will begin with a personal story of a 3x cancer
survivor and how with the assistance of great coworkers and collaborators an
effort has been made to fight back against this disease by studying the
chemistry and anti-cancer biology of gadolinium(III) texaphyrins.
Texaphyrins were the first of the so-called expanded porphyrins--larger
analogues of heme pigments--to stabilize a 1:1 complex with a metal cation.
Subsequently, and continuing as a focus today, an effort has been made in
our
laboratories and those of many others to create additional expanded
porphyrins.
Hundreds are now known. Several from our laboratory have proved useful at
stabilizing actinide cation complexes.
Recently, efforts have been made to create so-called immunogenic cell death
promoters designed to prevent cancer recurrence based on redox-active
gold(I) carbenes. An introduction to this new research direction will be
included in this lecture, as well new work involving the development of
expanded porphyrins and ExJade as ligands for the lanthanides and actinides.
Collaborations with a number of groups, including those of Drs. Dongho Kim,
Andrew Gaunt, John Arnold, Stosh Kozimer, Jong Sung Kim, Shunichi Fukuzumi,
T.K. Chandrashekar, Dirk Guldi, Changhee Lee, Jan Jeppesen, Steffen Bähring,
Zahid Siddik, Rick Finch, Esther Maier, Zhengrong Cui, Dani Gibson, and
Tomas Torres, are gratefully acknowledged. Special thanks also go to
Jonathan F. Arambula, Gregory Thiabaud, Sajal Sen, Xiaofan Ji, James
Brewster, and Daniel Mangel. Early funding came from the US NIH and the
CPRIT, with current support provided by InnovoTEX, Inc. and the Robert A.
Welch Foundation.
References
- Sessler, J. L.; Murai, T.; Lynch, V.; Cyr, M. J. Am. Chem. Soc. 1988, 110, 5586-5588.
- Brewster, J. T. II, Mangel, D. N.; Gaunty, A. J.; Saunder, D. P.; Zafa, H.; Lynch, V. M.; Boreen, M. A.; Garner, M. E.; Goodwin, C. A. P.; Settineri, N. S.; Arnold, J.; Sessler, J. L. J. Am. Chem. Soc. 2019, 141, 17867.
- Thiabaud, G.; He, G.; Sen, S.; Shelton, K. A.; Baze, W. B.; Segura, L.; Alaniz, J.; Macias, R. M.; Lyness, G.; Watts, A. B.; Kim. H. M.; Lee, H.; Cho, M. Y.; Hong, K. S.; Finch R.; Siddik, Z. H.; Arambula, J. F.; Sessler, J. L. Proc. Natl. Acad. Sci. USA 2020 117, 7021.
- Sen, S.; Hufnagel, S.; Maier, E. Y.; Aguilar, I.; Jayaraman, S.; DeVore, J. E.; Lynch, V. M.; Aramugam, K.; Cui, Z.; Sessler, J. L.; Arambula, J. F. J. Am. Chem. Soc. 2020, 142, 20536.
- Chen, J.; Sedgwick, A. C.; Sen, S.; Ren, Y.; Sun, Q.; Chau, C.; Arambula, J. F.; Sarma, T.; Song, L.; Sessler, J. L.; Liu, C. Chem. Sci. 2021, 12, 9916.
Biography
Prof. Jonathan L. Sessler was born in Urbana, Illinois, USA on
May
20, 1956. He received a B.S. degree (with Highest Honors) in chemistry in 1977
from
the University of California, Berkeley. He obtained a Ph.D. in organic chemistry
from Stanford University in 1982 (supervisor: Professor James P. Collman). He
was a
NSF-CNRS and NSF-NATO Postdoctoral Fellow with Professor Jean-Marie Lehn at
L'Université Louis Pasteur de Strasbourg, France. He was then a JSPS Visiting
Scientist in Professor Tabushi's group in Kyoto, Japan. In September, 1984 he
accepted a position as Assistant Professor of Chemistry at the University of
Texas
at Austin, where he is currently the Doherty-Welch Chair. Dr. Sessler has
authored
or coauthored over 870 research publications, written two books (with Dr. Steven
J.
Weghorn and Drs. Philip A. Gale and Won-Seob Cho, respectively), edited two
others
(with Drs. Susan Doctrow, Tom McMurry, and Stephen J. Lippard, Placido Neri and
Mei-Xiang Wang), and been an inventor of record on over 80 issued U.S. Patents.
To
date, Dr. Sessler’s work has been featured on more than 50 journal or book
covers.
His current WoS H-index is 114. From 2008-2019 Dr. Sessler served as an
Associate
Editor for ChemComm. Dr. Sessler was a co-founder (with Dr. Richard A. Miller)
of
Pharmacyclics, Inc., which was acquired by AbbVie for $21B in 2015. His
texaphyrin
technology is now the basis for a new company, InnovoTex, Inc. Dr. Sessler has
served as the co-organizer of several international conferences in porphyrin,
supramolecular, and macrocyclic chemistry and numerous American Chemical Society
symposia. In addition to English, he speaks French reasonably well, as well as
Hebrew and Spanish, and knows a little bit of German, Japanese, and Korean. Dr.
Sessler’s work has been recognized with several awards, including the American
Chemical Society Cope Scholar Award, the Royal Society of Chemistry Centenary
Prize,
the Southwest Regional American Chemical Society Award, the Molecular
Sensors-Molecular Logic Gates Award, the CASE award, and the Hans Fischer Award.
He
is a member of the U.S. National Academy of Inventors and was named Inventor of
the
Year at The Univ. of Texas at Austin in 2016. Dr. Sessler received the 2018
Thomas
Dougherty Award in Photodynamic Therapy from the Society of Porphyrins and
Phthalocyanines. In 2019, he received the C. David Gutsche Award in Calixarene
Chemistry and the Foreign Associate Award of the Asian Society for Porphyrins
and
Phthalocyanines. Dr. Sessler was elected a member of the European Academy of
Sciences in 2019. That same year he was named The University of Texas Co-op
Career
Research awardee, which is the highest prize given for research at his home
institution. In 2020 he received a Pioneer Award from The American Institute of
Chemists and in 2021 he received the Ronald Breslow Award in Biomimetic
Chemistry
from the American Chemical Society. Dr. Sessler is a Fellow of the American
Chemical
Society, the Royal Chemical Society, and of the American Association for the
Advancement of Science. He was elected to the US National Academy of Sciences in
April of 2021 and the American Academy of Arts and Sciences in April of 2022. He
received the Mond-Nyholm award from the Royal Society of Chemistry that same
year.
Info
Department of Chemistry, The University of Texas at Austin
Email: sessler@cm.utexas.edu
Junlong Zhang
Professor
Peking University
Ga(III) predrugs
Abstract
The trivalent Ga(III) shares most chemical properties except redox activity
with Fe(III), so that it acts as a competitive inhibitor of Fe(III) in the
human body, which contributes to its antineoplastic activity. As an Fe(III)
mimic, Ga(III) can be uptaken into cells through transferrin and be stored
in ferritin. Furthermore, it disrupts Fe-dependent processes by occupying
the Fe(III) sites in biomolecules, for example, inhibiting the activity of
ribonucleotide reductase and Fe-containing proteins in the respiratory
chain. However, Ga(III) speciation in the circulatory system is not clear,
the efforts to prevent the hydrolysis and precipitation of Ga(III) ions
offer multiple functions and anticancer mechanisms. In this talk, we will
report our recent progress on development of Ga(III) predrugs.
Biography
Jun-Long Zhang received his PhD from the University of Hong Kong (2005).
After postdoctoral research at the University of Illinois at
Urbana-Champaign (2008), he started his independent academic career at
Peking University and now is a full professor. Professor Zhang's research
focuses on bioinorganic chemistry, and metal diagnostics and medicines. He
has received several honors, including a Wiley-ACES Excellent Young
Professor Award, a Distinguished Lectureship Award (Chemical Society of
Japan), being named an Emerging Investigator in Bioinorganic Chemistry
(American Chemical Society), and a Chemistry Europe Early Career Award. He
was the winner of the inaugural AsBIC James Hoeschele Award (2020).
Info
Peking University
Email: zhangjunlong@pku.edu.cn
Justin Wilson
Professor
Cornell University
Developing and Understanding Rhenium Anticancer Agents
Abstract
Despite the clinical success and proven efficacies of the conventional
platinum-based drugs cisplatin, carboplatin, and oxaliplatin, these drugs
suffer from a number of challenges that limit their more widespread
therapeutic potential. These limitations, including toxic side effects and
susceptibility to cancer drug resistance mechanisms, have prompted
researchers to explore alternative metal complexes as anticancer agents. In
this presentation, an overview of our work on the development and
understanding of rhenium-containing organometallic complexes as potential
drug candidates is discussed. We will disclose our discovery that a wide
range of rhenium(I) tricarbonyl complexes exhibit potent in vitro anticancer
activity via diverse biological mechanisms of action. Furthermore, several
classes of rhenium(I) tricarbonyl complexes that we have investigated
undergo photochemical processes that can be harnessed to trigger cancer cell
death selectively upon irradiation or can be used for imaging applications.
For this class of compounds, we have carried out detailed biological studies
to determine their mechanisms of action. Our results indicate that subtle
structural modifications of these compounds can lead to significant changes
in their biological properties. Lastly, in vivo studies will be presented,
demonstrating that the potential of these compounds as anticancer drug
candidates exists beyond in vitro cellular experiments.
Biography
Justin Wilson obtained his B.S. in chemistry from UC Berkeley in 2008, have
carried out undergraduate research in the lab of Prof. Jeff Long. He then
went to pursue doctoral under the mentorship of Prof. Stephen J. Lippard at
the Massachusetts Institute of Technology (Cambridge, Massachusetts USA).
His thesis was focused on the design and discovery of novel platinum-based
anticancer agents. After earning his Ph.D. in 2013, Justin then carried out
postdoctoral studies as a Seaborg Institute Postdoctoral Fellow at Los
Alamos National Laboratory (Los Alamos, New Mexico USA) under the guidance
of Dr. Eva Birnbaum. His postdoctoral research was on the radiochemistry of
therapeutic alpha-emitting radionuclides. Since assuming his independent
position as an assistant professor at Cornell University (Ithaca, New York
USA) in 2015, Justin’s research program has focused on several different
aspects of inorganic medicinal chemistry. His research group is working on
projects involving targeted radionuclide therapy, metal-based inhibitors of
mitochondrial calcium uptake, and novel organometallic anticancer agents.
His work has been recognized by several awards, such as a 2018 NSF CAREER
Award, a 2019 Cottrell Research Scholar Award, the 2019 ACS Division of
Inorganic Jonathan L. Sessler Fellowship for Emerging Leaders in
Bioinorganic and Medicinal Inorganic Chemistry, the 2020 Edward Stiefel
Young Investigator Lecture Award at the Metals in Biology Gordon Research
Conference, and the 2022 National American Chemical Society Harry Gray Award
for Creativity in Inorganic Chemistry by a Young Investigator. In 2021,
Justin was promoted to the role of Associate Professor with indefinite
tenure.
Info
Associate Professor Department of Chemistry and Chemical Biology Cornell
University
Email: jjw275@cornell.edu
Taotao Zou
Professor
Sun Yat-Sen University
Towards Targeted Anti-Cancer Metal Complexes: from Modulation of the
Chemical Reactivity to Metalloimmunotherapy
Abstract
Metal complexes constitute one of the important types of cancer therapy but
suffer from low in vivo activity and toxic side effects. An effective way to
improve their therapeutic efficacy is to develop new type of metal complexes
with high tumor specificity or to identify new drug target based on
phenotype screening. Among them, gold complexes have been identified as
highly promising candidate for their different anti-cancer mechanisms
compared to cisplatin, and therefore they can potentially overcome drug
resistance issue of platinum drugs. In order improve the specificity of gold
towards the enzyme target-thioredoxin reductase and to meanwhile overcome
the off-target bindings, we developed a series of photo-responsive
cyclometalated gold(III) complexes containing hydride or alkyl ligands. Upon
light irradiation, the auxiliary ligands were released leading to Au-S bond
formation, and the photocytotoxicity was significantly increased by up to
>400-fold. Alternatively, we used a bioothogonal activation approach based
on transmetallation to activate gold complexes, giving similar tumor
specificity. In addition, we have identified a new type of Ir(III)-based
immunogenic cell death (ICD) inducer. Based this compound, we developed a
chemical biology probe and identified BiP as a key target that is engaged in
ICD. More importantly, other ICD inducers, such as KP1339, oxaliplatin, and
mitoxantrone were also found to engage BiP interaction, suggesting BiP as a
general target for ICD. We believe these works may be helpful in the design
of new metal complexes for targeted cancer therapy.
References
- Xiong, X.; Huang, K.-B.; Wang, Y.; Cao, B.; Luo, Y.; Chen, H.; Yang, Y.; Long, Y.; Liu, M.; Chan, A. S. C.; Liang, H.; Zou, T. J. Am. Chem. Soc. 2022, 144, 10407-10416.
- Xiong, X.; Liu, L.-Y.; Mao, Z.-W.; Zou, T. Coord. Chem. Rev. 2022, 453, 214311.
- Jiang, J.; Cao, B.; Chen, Y.; Luo, H.; Xue, J.; Xiong, X.; Zou, T. Angew. Chem. Int. Ed. 2022, 61, e202201103.
- Long, Y.; Cao, B.; Xiong, X.; Chan, A. S. C.; Sun, R. W.-Y.; Zou, T. Angew. Chem. Int. Ed. 2021, 60, 4133-4141.
- Luo, H.; Cao, B.; Chan, A. S. C.; Sun, R. W.-Y.; Zou, T. Angew. Chem. Int. Ed. 2020, 59, 11046-11052.
Biography
Taotao Zou is a professor in School of Pharmaceutical Sciences of Sun
Yat-Sen University. He obtained the bachelor degree in chemistry from Wuhan
University in June-2010. Thereafter he went to The University of Hong Kong
(HKU) to go after his PhD study under the supervision of Professor Chi-Ming
Che and obtained the degree in Feb-2015. After that, he has been a postdoc
fellow for three years at the University of Warwick with Prof. Peter J
Sadler, at HKU with Prof. Chi-Ming Che, and at The Scripps Research
Institute with Profs. Xiang-Lei Yang and Paul Schimmel. Taotao has been an
Assistant Professor in School of Science and Engineering of The Chinese
University of Hong Kong, Shenzhen during Mar 2018 to Jul 2018, and he is now
a full professor in School of Pharmaceutical Sciences of Sun Yat-Sen
University since Jul 2018. His research interests lie at the interface of
chemistry and biology, particularly, medicinal chemistry and chemical
biology of metal complexes, including anti-cancer compounds with in vitro
and in vivo activities, immunogenic cell death inducers, drug target
identification. His research has been recognized by local and international
awards, such as AsBIC Graeme Hanson Early Career Award, SciFinder Future
Leaders, Li Ka Shing Prizes, Hong Kong Young Scientist Awards, Finalist of
Reaxys PhD Prize and Springer Theses Prize.
Info
School of Pharmaceutical Sciences, Sun Yat-Sen University
Email: zoutt3@mail.sysu.edu.cn
Maria V. Babak
Professor
City University of Hong Kong
Targeting triple-negative breast cancer with rationally designed
gold-metformin prodrugs
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of
breast cancer, characterized by an aberrant metabolic phenotype with high
metastatic capacity, resulting in poor patient prognoses and low survival
rates. We designed a series of novel AuIII cyclometalated prodrugs of
energy-disrupting Type II antidiabetic drugs namely, metformin and
phenformin. Prodrug activation and release of the metformin ligand was
achieved by tuning the cyclometalated AuIII fragment. The lead
complex 3met was 6000-fold more cytotoxic compared to uncoordinated
metformin and significantly reduced tumor burden in mice with aggressive
breast cancers with lymphocytic infiltration into tumor tissues. These
effects was ascribed to 3met interfering with energy production in TNBCs and
inhibiting associated pro-survival responses to induce deadly metabolic
catastrophe.
References
- M.V. Babak,* W. H. Ang* et al. Angew. Chem. Int. Ed., 2021, 60, 24, 13405-13413.
Biography
Dr Maria (Masha) Babak is an assistant professor at City University of Hong
Kong and principal investigator at Drug Discovery Lab. She completed her
Ph.D in bioinorganic chemistry at the University of Vienna (2014), mentored
by Prof. Bernhard K. Keppler and Prof. Christian G. Hartinger . In 2015-2020
Dr Babak worked as a postdoctoral research fellow at National University of
Singapore, mentored by Prof. Wee Han Ang, where she developed a true passion
for drug discovery and drug target identification. Subsequently, Dr Babak
completed the High Impact Cancer Research Program at Harvard Medical School
in Boston. Dr Babak’s research interests lie at the interface of chemistry,
biology and medicine and focus on the discovery and preclinical development
of anticancer drugs for resistant and aggressive cancers with limited
treatment options.
Info
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong,
83 Tat Chee Avenue, Hong Kong SAR, 999077, People's Republic of China
Email: mbabak@cityu.edu.hk
Jim A Thomas
Professor
University of Sheffield
Luminescent d6-metal complexes as bioprobes, therapeutics and
theranostics
Abstract
Luminescent polypyridyl ruthenium complexes that interact with biomolecules
are much studied as potential cell probes.1 We have identified in-cell
probes for specific DNA structures through conventional optical techniques
such as confocal microscopy. However, using SIM and STED nanoscopy, 3-D
resolutions below 40 nm have been accomplished,2 and initial single-molecule
studies have been reported.
Through simple structural modulations STED-compatible, potent
therapeutics and phototherapeutics have been synthesized.
References
- M. R. Gill and J. A. Thomas, Chem Soc Rev, 2012, 41, 3179.
(a)S. Sreedharan, M. R. Gill, E. Garcia, H. K. Saeed, D. Robinson, A. Byrne, A. Cadby, T. E. Keyes, C. Smythe, P. Pellett, J. Bernardino de la Serna and J. A. Thomas, J. Am. Chem. Soc., 2017, 139, 15907.(b) F. Dröge, F. F. Noakes, S. A. Archer, S. Sreedharan, A. Raza, C. C. Robertson, S. Macneil, J. W. Haycock, H. Carson, A. J. H. M. Meijer, et al., J. Am. Chem. Soc 2021, 143, 20442.
- M. D. Newton, S. D. Fairbanks, J. A. Thomas, D. S. Rueda, Angew. Chemie - Int. Ed. 2021, 60, 20952.
- M. R. Gill, P. J. Jarman, S. Halder, M. G. Walker, H. K. Saeed, J. A. Thomas, C. Smythe, K. Ramadan, K. A. Vallis, Chem. Sci. 2018, 9, 841. (b) P. J. Jarman, F. Noakes, S. Fairbanks, K. Smitten, I. K. Griffiths, H. K. Saeed, J. A. Thomas, C. Smythe, J. Am. Chem. Soc. 2018, 141, 2925.
- S.A. Archer, A. Raza, F Dröge, C. Robertson, A. J. Auty, D. Chekulaev, J. A. Weinstein, T. Keane, A. J. H. Meijer, J. W. Haycock, S. MacNeil, J. A. Thomas, Chem. Sci. 2019, 10, 3502. (b) A. Raza, S. A. Archer, S. D. Fairbanks, K. L. Smitten, S. W. Botchway, J. A. Thomas, S. MacNeil, J. W. Haycock, J. Am. Chem. Soc. 2020, 142, 4639.
- M. R. Gill, P. J. Jarman, V. Hearnden, S. D. Fairbanks, M. Bassetto, J. Palmer, K. R. Ayscough, J. A. Thomas, C. Smythe, Angew. Chemie - Int. Ed. 2022, DOI 10.1002/anie.202117449. (b) . A Raza, S. A. Archer, J. A. Thomas, S. MacNeil, J. W Haycock, Ms submitted.
Biography
Prof. Jim A Thomas was born in Cardiff, UK and received his undergraduate
education at the University of Reading. After a period as a secondary school
teacher in the UK, he taught for two years at a community school in rural
Kenya through a contract organized by the UK development agency VSO. On
returning to the UK obtained a Ph.D. in inorganic chemistry from University
of Birmingham in 1993 (supervisor: Professor Jon McCleverty). After
postdoctoral fellowships worked with the Nobel Laureate, Prof Jean-Marie
Lehn (Strasbourg) he arrived in Sheffield to work with Prof Chris A Hunter,
FRS.
In 1995 he was awarded a Royal Society University Research
Fellowship and since then he has stayed in Sheffield. He has published more
than ~135 papers in refereed journals, leading to a H-index is 41. Research
in his group focusses on oligonuclear d6-metal ion complexes that recognize
ions, bio-ions, and biomolecules. This work has led to the develop on novel
cell probes, therapeutics and theranostics. His work on metal complex based
antimicrobials has led to a prize-winning spin-out company, Metallobio Ltd
(https://www.metallobio.com/).
Info
Dept of Chemistry, University of Sheffield
Email: james.thomas@shef.ac.uk
Xiaoyong Wang
Professor
Nanjing University
Platinum complexes as chemoimmunotherapeutic agents to enhance antitumor
efficacy
Abstract
Antitumor chemoimmunotherapy is a new strategy to treat tumors through the
combination of immunotherapy and chemotherapy taking advantage of
synergistic effect. Platinum drugs are important antitumor chemotherapeutic
agents, but have serious toxic side effects and drug resistance. Recent
studies found that some platinum complexes not only kill tumor cells
directly, but also participate in the regulation of immune processes through
various mechanisms. The combination of chemotherapy and immunotherapy
significantly improve the antitumor effect of platinum complexes.
Chemotherapeutic drugs may reduce the immune escape of tumor cells by
affecting the interaction between tumor cells and host cells. Platinum
complexes are involved in immune regulation through two pathways: (1)
activating immune responses or immune effectors; (2) relieving or
alleviating immune suppression. For example, coupling platinum complexes
with immunocompetent molecules can trigger immunogenic cell death (ICD) in
addition to inducing conventional apoptosis; combining platinum complexes
with immune checkpoint inhibitors can enhance antitumor immune response of T
cells and achieved remarkable chemoimmunotherapeutic effects. In summary,
the combination of chemotherapeutic agents and immunotherapeutic agents can
produce powerful synergistic effects. The antitumor efficacy of
chemoimmunotherapy is better than that of monotherapy. Platinum conjugates
not only enhance the antitumor effect by making use of the body’s immune
response, but also reduce the drug dose and toxic side effects. As a new
direction for the design of platinum antitumor drugs, platinum-based
chemoimmunotherapeutic agents are creating great opportunities for the
discovery of novel antitumor drugs.
Biography
Xiaoyong Wang: Professor of medicinal chemistry & biochemistry at the State
Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences,
Nanjing University. He received his B. Sc. degree in chemistry in 1986 at
Northwest Normal University, M. M. Sc. degree in medicinal chemistry in 1994
at Shandong University, and Ph. D. degree in 2003 at Nanjing University,
where he completed his postdoctoral research in 2005. His research interests
mainly lie in the field of inorganic medicinal chemistry and chemical
biology, particularly in the design and mechanism of platinum-based
anticancer drugs.
Info
State Key Laboratory of Pharmaceutical Biotechnology, School of Life
Sciences, Nanjing University
Email: boxwxy@nju.edu.cn
Nils Metzler-Nolte
Professor
Ruhr University Bochum
New Chemistry of Organometallic Rhenium Complexes for Drug Development
Abstract
Today, there are numerous examples for medicinal application of metal
complexes especially of the heavier transition metals. Following the success
of the Pt-derived metallodrugs (e.g. Cisplatin) and Au complexes (e.g.
Auranofin), other elements moved into the spotlight, such as Ru and Ir for
antitumor-active compounds and imaging purposes, respectively. In an attempt
to further broaden the range of useful metals for biomedical purposes, our
group has explored applications of Re compounds in cell biology and
biomedical research.
Re in the oxidation state +I is a d6 metal center. As such, we
expected favourable imaging parameters. Indeed, complexes with a suitable N3
ligand set derived from bis(picolyl)amine and a Re(CO)3 core proved to have
very favourable properties as cellular imaging agents. By tethering the
ligand to suitable targeting peptides, we were able to demonstrate good
cellular uptake and intracellular localization by fluorescence microscopy.[]
The imaging properties (phosphorescence lifetime and quantum yield) could be
further optimized by modifying the ligand set. Most importantly, the best
compounds were obtained with an unsymmetrical ligand set containing
quinoline and phenanthridine rings on the chelating tridentate ligand. Upon
excitation at 350 nm, the complexes commonly emit in the orange range (max
> 560 nm) of the visible spectrum, with large Stokes shifts > 20 nm. By
colocalization imaging with commercial dyes, a predominant localization in
the endoplasmatic reticulum (ER) was shown.
Interestingly, some of these complexes also displayed high
cytotoxicity against a range of mammalian cells. The mechanism of cell death
was elucidated by resistance breaking profiling and gene expression
analysis, with activation of both, the extrinsic and the intrinsic apoptotic
pathway.3 Finally, modifications of the ligand set around the Re center
revealed some very interesting new bioactive Re complexes with
N-heterocyclic carbene (NHC) ligands.4 In total, these complexes should well
add to the growing toolbox of organometallic complexes for biomedical
applications.
References
- L. J. Raszeja, A. Maghnouj, S. Hahn, N. Metzler-Nolte, ChemBioChem, 12 (2011) 371.
- L. J. Raszeja, D. Siegmund, A. L. Cordes, J. Güldenhaupt, K. Gerwert, S. Hahn, N. Metzler-Nolte, Chem. Commun., 53 (2017) 905.
- M. König, D. Siegmund, L. J. Raszeja, A. Prokop, N. Metzler-Nolte, MedChemComm, 9 (2018) 173.
- D. Siegmund, N. Lorenz, Y. Gothe, C. Spies, P. Prochnow, P. Nuernberger, J. E. Bandow, N. Metzler-Nolte, Dalton Trans., 46 (2017) 15269.
- G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem., 54 (2011) 3; G. Gasser, N. Metzler-Nolte, Curr. Opinion Chem. Biol. 16 (2012) 84; C. G. Hartinger, N. Metzler-Nolte, P. J. Dyson, Organometallics 31 (2012) 5677.
Biography
Prof. Nils Metzler-Nolte was born in Hamburg, Germany in 1967. After
studying chemistry at the Universities of Hamburg, Freiburg and Munich,
he graduated from Ludwig-Maximilians University Munich. He obtained a
Ph.D. degree in inorganic chemistry from the same University in 1994
(supervisor: Professor Heinrich Nöth), working on novel boron compounds
for material science applications. After a postdoc with Malcolm Green in
Oxford, UK, Nils Metzler-Nolte obtained his first independent position
at the Max-Planck Institute for Bioinorganic Chemistry in Mülheim / Ruhr
in Germany. He became Associate Professor for Medicinal and Bioinorganic
Chemistry at the University of Heidelberg in 2000. He then moved to his
current position as Full Professor and Chair of Inorganic Chemistry at
Ruhr University Bochum in 2006. In Bochum, he was Speaker (2009 – 2012)
of the Ruhr University Research School, a University-wide Graduate
Program that was funded by the German Excellence Initiative since 2006.
He also served as Vice President for Early Career Researchers and
International Affairs of Ruhr University from 2010 to 2012 and was
subsequently Dean of his Faculty between 2014 – 2018.
Professor Metzler-Nolte has published more than 250 papers and review
articles in SCI journals such as Nature Chem Biol, PNAS, J Am Chem Soc,
Angew Chem Int Ed, Chem Sci, J Med Chem, Chem Comm et al. His papers have
been cited well over 12 000 times, and his current WoS H-index is 56. His
reviews on the Bioorganometallic Chemistry of Ferrocene (Chem Rev in 2004)
and on Medicinal Organometallic Chemistry (J Med Chem in 2011) have both
been cited well over 1000 times. He served as Associate Editor for Dalton
Transactions, and is currently Chief Editor of the Journal of Biological
Inorganic Chemistry (JBIC), the official journal of the Society of
Biological Inorganic Chemistry. Prof. Metzler-Nolte is or was also member of
the Editorial Advisory Boards of several journals, including Chem Sci, Eur J
Inorg Chem, Organometallics, Applied Organometallic Chemistry, and others.
For his outstanding academic achievements, he was awarded several prizes and
honorary titles, including the Fellow of the Royal Society of Chemistry
(FRSC), the Karl-Ziegler Fellowship of the German Chemical Society, the
Julius-van-Haast Award by the Royal Society of New Zealand, and most
recently the Elsevier Award for Outstanding Achievements in
Bioorganometallic Chemistry. He has organized several national and
international meetings, e.g. the Fifth International Symposium on
Bioorganometallic Chemistry in 2010 in Bochum, and was Co-Chair of the 2016
Gordon Research Conference on Metals in Medicine (together with Prof. Kathy
Franz, Duke University, USA). Totally he has so far mentored close to 100
graduates (Master and PhD researchers), and several of the PhDs and
post-docs from his group now hold leading academic positions or
professorships themselves.
Info
Ruhr University Bochum, Inorganic Chemistry I – Bioinorganic Chemistry,
Bochum, Germany.
Email: nils.metzler-nolte@rub.de
Hongke Liu
Professor
Nanjing Normal University
New Strategies of Metal-Arene Anticancer Complexes
Abstract
The use of new methods and new technologies to develop new anti-cancer
strategies, new targets and new mechanisms is a frontier scientific problem
in anti-cancer research, as well as a major challenge and opportunity.
Natural product active ingredients such as rhein, curcumin and
glycyrrhetinic acid have good anti-cancer and antibacterial activities. Our
research group selects chemical modified natural product active ingredients
as ligands, we designed and synthesized a series of novel metal-arene and
other metal complexes with multiple targeting of cells, tissues, and
subcellular organelles. By introducing active ingredients from natural
products, the anticancer activity of the complexes was improved. We have
developed a novel strategy---Bioorthogonally-Catalyzed Lethality (BCL) to
generate efficient anticancer species between two non-toxic components only
within cancer cells and tumors without external catalysts, realized the
precise and efficient anticancer chemotherapy. The BCL strategy uses tumors
as manufacturing factories to generate a highly potential tumor-targeted
drug Ru-rhein, which can selectively kill cancer cells and tumors in
tumor-bearing mice, while no toxicity on normal cells (Figure 1).
Osmium-arene complexes showed high phototoxicity and cancer cell targeting,
and their photochemical reaction mechanism, phototoxicity mechanism and
mechanism of overcoming drug resistance were studied (Figure 1).
References
- Su,Y., Liu, H.-K., and Su Z. et al., Chem. Sci., 2022, 13, 1428-1439.
- Liu, L., Su Z., Zhao, J., Mao, Z.-W., Huang, Y., Liu, H. K. et al., Chin. J. Chem., 2022, 40, 1156-1164.
- Zhao, J., Liu, H. K., Guo, Z. J. et al., Natl. Sci. Rev., 2021, DOI: 10.1093/nsr /nwaa286.
- Zhang, B, Chen, G., Liu, H. K. and Qian, Y. et al., ACS Sens. 2021, 6, 863-870.
- Liu, H. K., and Qian, Y. et al., Chem. Commun., 2021, 57, 1931-1934.
- Su Z., Mao, Z.-W., Liu, H. K., Sadler, P. J. et al., Inorg Chem., 2021, 60, 17450-17461.
- Ge, C., Liu, H.-K. and Qian, Y. et al., Analyst, 2021, 146, 3510-3515.
- Zhu, H.-L., Liu, H.-K. and Qian, Y. et al., Adv. Sci., 2019, 6, 1900341.
- Liu, H.-K., Guo Z. j., He W. et al., Angew. Chem. Int. Ed., 2019, 58, 12661.
- Liu, H.-K., Hao Q. and Su Z. et al., J. Mater. Chem. A, 2019, 7, 24964.
Biography
Prof. Hongke Liu was born in Shannxi, China. He obtained bachelor's,
master's and doctoral degrees from Northwestern University (1988 and 1993)
and Nanjing University (1999), respectively. He was a visiting professor at
the University of Warwick (2014-2015), a researcher fellow at the School of
Chemistry at the University of Edinburgh (2003-2005), a full-time researcher
associates at the School of Chemistry at the University of Toledo
(2001-2003), and a postdoctoral fellow at Sun Yat-Sen University
(1999-2001). He is a professor and doctoral supervisor, and deputy director
of the professor committee of the School of Chemistry and Materials Science,
Nanjing Normal University. He awarded several honorary titles, including
Jiangsu Province 333 Engineering Talents (2011 and 2014), Jiangsu Province
Six Talent Peaks - New Medical Talents. He is a member of the Chemical
Biology and Functional Materials Professional Committee of the Jiangsu
Society of Chemistry and Chemical Engineering, and a member of the
Biofunctional Materials Professional Committee of the Jiangsu Composite
Materials Society. He is currently the deputy director of Jiangsu Sports and
Rehabilitation Materials Engineering Technology Research Center.
His research is mainly focus on the design and synthesis of
novel metal-arene complexes and integrated diagnosis agents, their
anticancer activity and mechanism. A "bioorthogonal catalytic lethal" (BCL)
strategy is proposed to manufacture targeted anticancer drugs in tumor cells
and in vivo through bioorthogonal reactions, which will help for precise and
efficient treatment of diseases. He has awarded over 5 projects of the
National Natural Science Foundation of China (1 key project and 4 general
projects); more than 10 provincial and ministerial-level projects and
enterprise projects, and 2 provincial-level talent projects. He has
published more than 120 corresponding author or first author academic papers
in international journals such as Acc. Chem. Res., NSR, PNAS, Angew. Chem.,
Adv. Sci. and Chem. Sci., and authorized 10 patents. He is a reviewer for
international journals such as JACS and Chem. Sci. In recent years, he has
been invited to give more than 60 keynote reports, invited reports and
branch chairpersons at international and national academic conferences.
Info
School of Chemistry and Materials Science, Nanjing Normal University
Email: liuhongke@njnu.edu.cn
Luigi Messori
Professor
University of Florence
Auranofin: Chemistry and Biology of a Fascinating Metal based Drug
Abstract
Auranofin (AF) is an established metal-based drug, in clinical use for the
treatment of rheumatoid arthritis since 1985, that is now being repurposed
for different therapeutic uses, in particular as an antimicrobial,
antiparasitic and anticancer agent.
We have focused our attention on the role of AF as a candidate anticancer
drug. The potent antiproliferative effects of auranofin against a variety of
cancer cells are now well documented; owing to its remarkable anticancer
actions and the favorable toxicity profile AF has entered clinical trials
for cancer treatment. Though the selenoenzyme thioredoxin reductase is
generally believed to be the primary target for auranofin, the actual
mechanisms through which AF induces cancer cell death are not fully
understood and still a matter of intense research. To disclose the molecular
mechanisms of auranofin in cancer cells we have started a systematic
research program including a series of omics determinations. In a first
study the effects of AF in A2780 human ovarian cancer cells were analyzed
through an NMR metabolomics approach [1]. Results pointed out a major
dysregulation in glutathione metabolism as the main effect of the treatment.
Subsequently, a combined proteomics and redox proteomics strategy was
implemented that highlighted several distinct cellular actions of auranofin
in the same cancer cell line [2]. The main achievements of this latter study
will be presented. The logical next step in this research project will be a
metallomics investigation aimed at determining the fate of gold inside
cancer cells. We are confident that a tight integration of the various omics
methods has the potential to provide a rather comprehensive picture of the
cellular effects of AF in cancer cells and reveal what the true biomolecular
targets for this fascinating gold drug are.
References
- V. Ghini, T. Senzacqua, L. Massai, T. Gamberi, L. Messori, and P. Turano, Dalton Transactions, 2021, 50, 6349
- G. Chiappetta, T. Gamberi, F. Faienza, X. Limaj, S. Rizza, L. Messori, G. Filomeni, A. Modesti and J. Vinh, Redox Biology, 2022, 52, 102294.
Biography
Luigi Messori was born in Florence, on March 25, 1958. PhD in Chemical
Sciences (1987), Assistant Professor in the C03X sector (General and
Inorganic Chemistry), Associate Professor in General and Inorganic Chemistry
(2004), he is a member of the Department of Chemistry, University of
Florence. Since 1994 he has taught General and Inorganic Chemistry and
Laboratory of General and Inorganic Chemistry to students belonging to the
Faculty of Agricultural Sciences and to the Faculty of Sciences, in
Florence. His main research interests are in the field of bioinorganic
chemistry. In a first phase he has been involved in the study of the
solution behavior of metalloproteins, with emphasis on metal carrier
proteins (transferrins and metallothionein) and on selected zinc enzymes
(carbonic anhydrase, carboxypeptidase), within the group of Prof. Bertini.
Later on, starting from 1995, his research interests moved to consider the
role of metal ions in medicine. In particular, he directed his attention
towards antitumor metal complexes (mainly ruthenium(III) and gold(III)
complexes) and to their interactions with nucleic acids and proteins.
The main topics of his research activity are the following: i)
Transferrin and the transport of ruthenium complexes; ii) Antiproliferative
gold(III) compounds. iii) Proteomics and the mode of action of anticancer
metallodrugs. iv) Thioredoxin reductase as a primary target for anticancer
gold compounds. v) Protein metalation by anticancer metallodrugs.
He has been involved in various COST actions dealing with
metal based drugs (D8, D20, D39, CM1105) with different roles. He has given
several lectures in Italy and abroad on the above topics. He is author of
more than 330 papers, published on international scientific journals, with
an h index of 64, and more than 14000 citations (Scopus data).
Info
METMED Laboratory, Department of Chemistry Ugo Schiff (DICUS), University
of Florence,
via della Lastruccia 3, 50019 Sesto Fiorentino (FI) -Italy
Email: luigi.messori@unifi.it
Jose Ruiz
Professor
University of Murcia
Dipyridophenazine iridium(III) complexes as mitochondria targeting PDT
agents
Abstract
Cyclometalated Ir(III) complexes have emerged as promising photosensitizers
(PSs) for photodynamic therapy (PDT), due to their convenient tunable
photophysical and photochemical properties that can be modified to obtain a
high reactive oxygen species (ROS) and 1O2 production. On the other hand,
cancer stem cells (CSCs) are considered the reason for chemotherapy
resistance, relapse, and metastasis, primarily due to their ability to
escape from the conventional chemotherapeutics and from the immune attack.[
L. V. Nguyen, R. Vanner, P. Dirks and C. J. Eaves, Nat. Rev. Cancer, 2012,
12, 133–143.] Current research suggests immunotherapeutic strategies that
target CSCs may improve the efficacy of cancer treatment when used in
combination with traditional cytotoxic therapies.[ A. Johnson, J.
Northcote-Smith and K. Suntharalingam, Trends in Chemistry, 2021, 3, 47–58.
] Immunogenic cell death (ICD) is an immunostimulatory form of cell death
that constitutes one of the methods by which antitumor drugs can induce a
tumor-targeting immune response.
Herein, we report some octahedral Ir(III) complexes based on a
benzimidazole backbone containing NH groups and the study of their mechanism
of action towards melanoma A375 cancer cells under blue light irradiation in
both normoxic and hypoxic conditions. IrL4 induces immunogenic cell death in
melanoma when the cells are irradiated by blue light, which could
synergistically enhance its anticancer efficiency. This Ir(III) complex
appears to be a promising CSCs-directed candidate for immunostimulation
phototherapy that could be able to overcome limitations connected with the
use of a number of conventional chemotherapeutics, suppressing side effects
with a selective activation only with light and fighting against acquired
resistance and metastasis of cancers such as melanoma.
Acknowledgements: This work was supported by funds from the
Czech Science Foundation (grant 21-27514S) and the Spanish Ministerio de
Ciencia e Innovación-Agencia Estatal de Investigación
(MCI/AEI/10.13039/501100011033) and FEDER funds (project
RTI2018-096891-B-I00).
References
- L. V. Nguyen, R. Vanner, P. Dirks and C. J. Eaves, Nat. Rev. Cancer, 2012, 12, 133–143.
- A. Johnson, J. Northcote-Smith and K. Suntharalingam, Trends in Chemistry, 2021, 3, 47–58.
- B. Englinger, C. Pirker, P. Heffeter, A. Terenzi, C.R. Kowol, B. K. Keppler and W. Berger, Chem. Rev., 2019, 119, 1519–1624.
- G. Vigueras, L. Markova, V. Novohradsky, A. Marco, N. Cutillas, H. Kostrhunova, J. Kasparkova, J. Ruiz and V. Brabec, Inorg. Chem. Front., 2021, 8, 4696–4711.
Biography
Prof. José Ruiz studied Chemistry at the University of Murcia (UMU) and
received the National Extraordinary Bachelor’s Degree Award by the Spanish
Ministry of Education. He received his PhD in Chemistry in 1984 at UMU.
Afterwards, he moved to the Sheffield University (UK), where he spent 2
years as a Post-doctoral Researcher in the P.M. Maitlis group. In 1987, he
got a permanent position as a Lecturer at UMU. Since 2002, he started his
independent career and drove his interest towards the field of Medicinal
Inorganic Chemistry. In 2007, he became Professor at UMU and founded the
Metallodrugs Discovery Group. He is also leader of the Non Conventional
Anticancer Metallodrugs Group at the IMIB (Murcian Institute of Biosanitary
Research). He is member of the ACS and has served as President of the
Spanish Society of Bioinorganic Chemistry (2017-2022).
Throughout his scientific career, he has authored 119
publications in peer-reviewed international journals, leading to more than
3,720 citations (1,370 in the last five years; WOS). His h-index is 36. In
the last ten years JRuiz has published 43 papers in the area of Inorganic,
Medicinal and Multidisciplinary Chemistry: e.g. 1× Angew. Chem., 3 × J. Med.
Chem., 3 × Coord. Chem. Rev., 5 × Chem. Commun., 4 × Inorg. Chem. Front., 4
× Chem. Eur. J., 1 × Eur. J. Med. Chem., 1 Biomacromolecules and 7 × Inorg.
Chem.
Some main achievements are:
1) The development of a successful divergent synthesis of
novel C,N-cyclometalated benzimidazole Ru(II) and Ir(III) anticancer
complexes with a handle for further functionalization (J. Med. Chem. 2015;
93 citations).
2) The design of theranostic agents based on d6 luminescent
Ir(III) complexes, including conjugates with receptor-binding peptides such
as the FDA-approved octeotride and its dicarba analogue (somatostatin
receptor-targeted; Chem. Comm. 2017; 39 citations).
3) The synthesis of photodynamic therapy agents such as the
Ir(III)-COUPY conjugate - with absorption and emission in the biocompatible
region (Angew. Chem. 2019; 90 citations).
His current research interest is focused on the design and
synthesis of d6 metal-based photosensitisers with novel mechanisms of action
(e.g. Inorg. Chem. Front. 2021, Chem. Commun. 2020, J. Med. Chem. 2021).
In addition, He has been invited to give many invited
lectures: e.g. EuroBIC Birmingham 2018; ICCC2018. Sendai (Japan);
Photochemistry School 2020 DIPC, Donostia (Spain); CulturChem Conference
(Graduate School) Sorbonne University, 2022; Research workshop of the Israel
Science Foundation "Metals in Medicine", Jerusalem, 2022. Prof. Ruiz has
developed numerous international collaborations with research groups such as
those headed by Brabec (Academy of Sciences of the Czech Republic, Brno),
Janiak (U. Düsseldorf), Ott (U. Braunschweig), Marchán (U. Barcelona),
Barone (U. Palermo), Glazer (U. Kentucky), and Gasser (PSL University,
París). He is a regular evaluator of scientific journals (e.g. Adv. Mater.,
J. Am. Chem. Soc., Chem. Sci., Chem Soc. Rev., Adv. Funct. Mater.,
Biomaterials), as well as of project proposals in competitive calls for
international agencies: e.g. Dutch Research Council, Agence Nationale de la
Researche (France), Deutsche Forschungsgemeinschaft (Germany), Israel
Science Foundation, State Investigation Agency (AEI, Spain), etc. JRuiz has
participated in the organization of many scientific meetings as the. AEBIN
biennials. He is currently the Head of the Department of Inorganic Chemistry
of UMU.
5 Key Recent Publications
- J. Bonelli, E. Ortega,..., N. Cutillas, J. Ruiz,* V. Marchan.* "Polyurethane-polyurea hybrid nanocapsules as efficient delivery systems of anticancer Ir(III) metallodrugs" Inorg. Chem. Front. 2022. 9, 2123; https://doi.org/10.1039/D1QI01542G Highlighted as a Front cover.
- A Photoactivated Ir(III) Complex Targets Cancer Stem Cells and Induces Secretion of Damage-associated Molecular Patterns in Melamoma Cells Characteristic of Immunogenic Cell Death G. Vigueras, L. Markova, V. Novohradsky, A. Marco, N. Cutillas, H. Kostrhunova, J. Kasparkova, J. Ruiz,* V. Brabec,* Inorg. Chem. Front. 2021, 8, 4696-4711d. DOI: 10.1039/d1qi00856k.
- Novel organo-osmium(II) proteosynthesis inhibitors active against human ovarian cancer cells reduce gonad tumor growth in Caenorhabditis elegans E. Ortega, F. J. Ballester, A. Hernández-García, S. Hernández-García, M. Alejandra Guerrero-Rubio, D. Bautista, M. D. Santana,* F. Gandía-Herrero,* J. Ruiz* Inorg. Chem. Front. 2021, 8, 141-155. DOI: 10.1039/C9QI01704F
- Ru(II) photosensitizers competent for hypoxic cancers via green light activation F.J. Ballester, E. Ortega, D. Bautista, M.D. Santana,* J. Ruiz* Chem. Commun. 2020, 56, 10301-10304. DOI: 10.1039/D0CC02417A.
- Towards Novel Photodynamic Anticancer Agents Generating Superoxide Anion Radicals: A Cyclometalated Ir(III) Complex Conjugated to a Far-Red Emitting Coumarin V. Novohradsky, A. Rovira, C. Hally, …, J. Ruiz* , …, V. Marchán,* Angew. Chem. Int. Ed. Engl. 2019, 58, 6311-6315. DOI: 10.1002/anie.201901268.
Info
Professor of Inorganic Chemistry Facultad de Quimica University of Murcia
Campus de Espinardo
Email: jruiz@um.es
Website: http://www.um.es/qcqo/jruiz_uk.htm
Day 2 (Aug 27, 2022)
Thomas J. Meade
Professor
Northwestern University
MR responsive and Theranostic Probes: Where are we going?
Abstract
We report a new series of MR contrast agents for tracking gene therapy in
vivo and to ultimately treat monogenic diseases. With mean survival rate of
5 years (and most cases are fatal) lysomal storage diseases (LSD) are among
the most dismal of prognosis in all of medicine. LSD’s represent a large
number of monogenetic diseases and while rare the prevalence is to
hemophilia. As monogenetic diseases with clearly defined genotype-phenotype
relations, lysosomal storage diseases are excellent candidates for gene
therapy. The transformative results documented in an adeno-associated virus
(AAV) gene therapy clinical trial in infants affected by spinal muscular
atrophy demonstrated unequivocally the potential of in vivo gene transfer to
treat monogenic neurological disorders.
To date there is a lack of non-invasive ways to determine
biodistribution or activity levels of these AAV therapies in patients. This
is a significant hinderance, leaving investigators guessing which organs or
structures are effectively treated and, due to the lag time associated with
clinical disease progression, this limitation ultimately impacts the
evolution of treatment modalities.
In order to overcome these limitations, we have developed a
new class of bioresponsive MR imaging agents to track enzymatic activity in
any organ, peripheral nervous system (PNS), or central nervous system (CNS)
over time. MR imaging is an ideal technique for the study of neurological
disorders.
Biography
Professor Meade is the Eileen M. Foell Professor of Cancer Research and The
Charles Deering McCormick Professor of Teaching Excellence. He is Professor
of Chemistry, Molecular Biosciences, Neurobiology, and Radiology. He
received his Master’s in biochemistry and a Ph.D. in inorganic chemistry and
after completing a NIH fellowship at Harvard Medical School, he was a
postdoctoral fellow at Caltech. In 1991 he became a faculty member in the
Division of Biology and the Beckman Institute at Caltech.
In 2002 he moved to Northwestern University, where he is the
Director of the Centers for Advanced Molecular Imaging (CAMI) and
Quantitative Bio-element Imaging (QBIC). His research focuses on
coordination chemistry and its application to bioinorganic problems that
include biological molecular imaging, electron transfer processes, the
inhibition of Zn finger transcription factors, and the development of
electronic biosensors for the detection of DNA and proteins. He has founded
six biotech companies and has more than 300 publications and holds 120
issued US patents.
Info
Departments of Chemistry, Molecular Biosciences, Neurobiology and
Radiology, Northwestern University, 2145 Sheridan Rd, Evanston IL, 60208,
USA
Email: tmeade@northwestern.edu
Jong Seung Kim
Professor
Korea University
Molecular prodrug engineering towards precision drug delivery system
Abstract
Breast cancer consists of heterogenic subpopulations, which determine
the
prognosis and response to chemotherapy. Among these subpopulations, a
very
limited number of cancer cells are particularly problematic. These
cells,
known as breast cancer stem cells (BCSCs), are thought responsible for
metastasis and recurrence. They are thus major contributor to the
unfavorable outcomes seen for many breast cancer patients. BCSCs are
more
prevalent in the hypoxic niche. This is an oxygen-deprived environment
that
is considered crucial to their proliferation, stemness, and
self-renewal,
but also one that makes BCSCs highly refractory to traditional
chemotherapeutic regimens. We report a small molecule construct, AzCDF,
that
allows the therapeutic targeting of BCSCs and which is effective in
normally
refractory hypoxic tumor environments. A related system, AzNap, has been
developed that permits CSC imaging. Several design elements are
incorporated
into AzCDF, including the CAIX inhibitor, acetazolamide (Az) to promote
localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a
hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a
readily
released therapeutic payload. This allows AzCDF to serve as a
hypoxia-liable
molecular platform that targets BCSCs selectively that decreases CSC
migration, retards tumor growth, and lowers tumorigenesis rates as
evidenced
by a combination of in vitro and in vivo studies. To the best of our
knowledge this is the first time a CSC-targeting small molecule has been
shown to prevent tumorigenesis in an animal model.
References
- J. H. Kim, P. Verwilst, J. Lee, M. Won, J. L. Sessler, J. Han, J. S. Kim, J. Am. Chem. Soc. 143, 14115-14124 (2021).
- M. Won, S. Koo, H. Li, J. Y. Lee, A. Sharma, J. S. Kim, Angew. Chem. Int. Ed. 60, 3196-3204 (2021).
- P. Jangili, N. Kong, J. H. Kim, J. Zhou, H. Liu, X. Zhang, W. Tao, J. S. Kim, Angew. Chem. Int. Ed. 61, e202117075 (2022).
- 4)S. Koo, M.-G. Lee, A. Sharma, M. Li, X. Zhang, K. Pu, S.-G Chi, J. S. Kim, Angew. Chem. Int. Ed. 61, e202110832 (2022).
Biography
Jong Seung Kim, FRSC, received his Ph. D. from the
Department
of Chemistry and Biochemistry at Texas Tech University in 1993. He has
worked at
University of Houston as a post-doc in 1994. Currently he is a full
professor in
Department of Chemistry at Korea University in Seoul. He has published about
530
papers in prestigious journals with h-index 106. His research interests are
application of organic chemistry in drug delivery and theranostics. He is a
member of the Korea Academy of Science and Technology. He has been selected
as a
Highly Cited Researcher since 2014.
Info
Department of Chemistry, Korea University
Email: jongskim@korea.ac.kr
Samuel G. Awuah
Professor
University of Kentucky
Transition metal-derived compounds to control mitochondrial dynamics
Abstract
Mitochondrial function, dynamics, structure and organization are integral
to maintaining mitochondrial homeostasis and an emerging biological target
in aging, inflammation, neurodegeneration, and cancer. The study of
mitochondrial function/structure and its implications remains challenging
due to the lack of available chemical tools for direct engagement,
particularly in a disease setting. Efforts in the Awuah laboratory are
geared toward the development of a transition metal-based approaches to
interrogate distinct mitochondrial targets or pathways. Specifically, the
design and synthesis of a series of gold complexes with unique spatial
geometries is of keen interest.
Biography
Prof. Awuah is an assistant professor of Chemistry and Pharmaceutical
Sciences at the University of Kentucky. Prior to joining the faculty at UK,
he obtained his undergraduate BS degree in Chemistry from KNUST in Ghana,
PhD from the University of Oklahoma under the research direction of Prof.
Youngjae You and trained as a postdoctoral associate under the guidance of
Prof. Stephen J. Lippard at MIT, where he worked on understanding the
mechanism of cisplatin and developed new next generation metallodrugs. Prof.
Awuah's current research focuses on metal-based approaches for intracellular
protein modification and development of clinically relevant therapeutics.
His drug discovery program is tailored towards disrupting protein-protein
interactions and elusive biological targets.
Info
assistant professor of Chemistry and Pharmaceutical Sciences at the
University of Kentucky
Email: awuah@uky.edu
Cai-Ping Tan
Professor
Sun Yat-Sen University
Action Mechanisms of Phosphorescent Anticancer Metal Complexes: Phase
Separation and Immunotherapy
Abstract
Multifunctional phosphorescent metal complexes, including cyclometallated
iridium(III) complex, polypyridine ruthenium(II) complexes and tricarbonyl
Re(I) complexes, have unique antitumor properties and rich photophysical and
photochemical properties (Fig. 1).[1] We designed a Ru(II) complex that can
induce and monitor the DNA phase separation simultaneously, and it realizes
real-time induction and tracking of DNA phase separation process in living
cells.[2] In order to interfere with iron homeostasis in cells, we designed
Re(I) complex with mitochondrial targeting and iron chelating properties,
and we found it can cause accumulation of iron in mitochondria and reshape
the epigenetic status of cancer cells.[3] We designed a endoplasmic
reticulum-targeted Re(I) complex and realized the semi-quantitative
detection of changes in viscosity during the autophagy process of the
endoplasmic reticulum by using two-photon phosphorescence lifetime
imaging.[4] We designed two phosphorescent iridium complexes with
ferrocene-modified diphosphine ligands. They can catalyse the Fenton
reaction, generate lipid peroxidation, induce ferropotis, and stimulate
cancer immune responses.[5] Recently, we designed two platinum complexes
containing triphenylamine ligands that could activate the cGAS-STING pathway
that regulates the innate immunity by photo-damaging DNA.[6] In conclusion,
our study shown the great prospects of the anticancer applications of
phosphorescent metal complexes.
References
- Tan, C. P.; Zhong, Y. M.; Ji, L. N.; Mao, Z. W. Chem. Sci., 2021, 12, 2357.
- Wang, W. J.; Mu, X.; Tan, C. P.; Wang, Y. J.; Zhang, Y. B.; Li, G. H.; Mao, Z. W. J. Am. Chem. Soc., 2021, 143, 11370.
- Pan, Z. Y.; Tan, C. P.; Rao, L. S.; Zhang, H.; Zheng, Y.; Hao, L.; Ji, L. N.; Mao, Z. W. Angew. Chem. Int. Ed., 2020, 59, 18755.
- Hao, L; Ling, Y. Y.; Pan, Z. Y.; Tan, C. P.; Mao, Z. W. Natl. Sci. Rev., 2022, DOI: 10.1093/nsr/nwab194.
- Wang, W. J.; Ling, Y. Y.; Zhong, Y. M.; Li, Z. Y.; Tan, C. P.; Mao, Z. W. Angew. Chem. Int. Ed., 2022, 61, e202115247.
- Ling, Y. Y.; Xia, X. Y.; Hao, L.; Wang, W. J.; Zhang, H.; Liu, L. Y.; Liu, W.; Li, Z. Y.; Tan, C. P.; Mao, Z. W. Angew. Chem. Int. Ed., 2022, DOI: 10.1002/anie.202210988.
Biography
Prof. Cai-Ping Tan was born in March 1981. She is a Professor in School of
Chemistry, Sun Yat-Sen University. She graduated from South China Normal
University with a bachelor's degree in 2002. In 2008, She graduated from Sun
Yat-Sen University with a Doctor's degree in Chemical Biology under the
supervision of Prof. Liang-Nian Ji. From 2008 to 2010, She was a
post-doctoral fellow in School of Life Sciences, Sun Yat-Sen
University. Since 2011, she served as a lecturer, associate professor and
professor in School of Chemistry, Sun Yat-Sen University. From 2016 to 2017,
she went to the University of Chicago as a visiting scholar in Prof. Chuan
He’ group. Her research interests are the anticancer properties of
multifunctional phosphorescent metal complexes integrating imaging and
therapy. She published over SCI 40 papers in the field of metallo-anticancer
agents, and some research results were published in JACS, Angew Chem, Nat
Sci Rev and Adv Sci.
Info
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of
Chemistry, Sun Yat-Sen University
Email: tancaip@mail.sysu.edu.cn
Kenneth Kam-Wing Lo
Professor
City University of Hong Kong
Strategic Designs of Photofunctional Transition Metal Complexes for
Cellular Imaging and Photocytotoxic Applications
Abstract
The applications of photofunctional transition metal complexes in
biosensing, bioimaging, and phototherapy have received considerable
attention. We are interested in the exploitation of the intriguing
photophysical and photochemical properties of transition metal polypyridine
complexes in the development of innovative diagnostic and therapeutic
reagents. The remarkable features of these complexes include their
environment-sensitive and long-lived emission and facile singlet
oxygen-photosensitization characteristics, which confer favorable diagnostic
and therapeutic capabilities, respectively, on these metal complexes. In
this lecture, I will describe our strategies in the design of
photofunctional rhenium(I), ruthenium(II), and iridium(III) polypyridine
complexes as bioimaging reagents and photocytotoxic agents through the
introduction of various functional pendants. I will explain how these groups
will endow the complexes with controllable photophysical and photochemical
properties, cellular uptake and organelle-targeting characteristics, and
photocytotoxic activity.
References
- Lo, K. K.-W. Acc. Chem. Res. 2020, 53, 32 – 44.
- Leung, P. K.-K.; Lo, K. K.-W. Chem. Commun. 2020, 56, 6074 – 6077.
- Leung, P. K.-K.; Lee, L. C.-C.; Yeung, H. H.-Y.; Io, K.-W.; Lo, K. K.-W. Chem. Commun. 2021, 57, 4914 – 4917.
- Leung, P. K.-K.; Lee, L. C.-C.; Ip, T. K.-Y.; Liu, H.-W.; Yiu, S.-M.; Lee, N. P.; Lo, K. K.-W. Chem. Commun. 2021, 57, 11256 – 11259.
- Zhu, J.-H.; Xu, G.-X.; Shum, J.; Lee, L. C.-C.; Lo, K. K.-W. Chem. Commun. 2021, 57, 12008 – 12011.
- Yip, A. M.-H.; Lai, C. K.-H.; Yiu, K. S.-M.; Lo, K. K.-W. Angew. Chem. Int. Ed. 2022, 61, e202116078.
Biography
Prof. Kenneth Lo obtained his BSc (1993) and PhD (1997) degrees at The
University of Hong Kong, and worked as a Croucher Foundation Postdoctoral
Research Fellow at University of Oxford (1997 – 99). He joined the
Department of Biology and Chemistry (currently Department of Chemistry) of
City University of Hong Kong in 1999 and became Professor in 2011. He
received the Asian and Oceanian Photochemistry Association Prize for Young
Scientist in 2005, the Chemical Society of Japan Distinguished Lectureship
Award in 2011, and a Croucher Foundation Senior Research Fellowship in 2015.
He served as an Associate Editor for RSC Advances from 2015 to 2020, and has
been an Associate Editor for Inorganic Chemistry since 2020. His research
interest is the utilization of luminescent transition metal complexes as
biomolecular and cellular probes, with a focus on the development of
intracellular sensors, bioimaging reagents, and photocytotoxic agents.
Info
Department of Chemistry, City University of Hong Kong, Tat Chee Avenue,
Hong Kong, P. R. China
Email: bhkenlo@cityu.edu.hk
Yangzhong Liu
Professor
University of Science and Technology of China
Protein Based Drug Delivery for Tumor Theranostics
Abstract
Cisplatin and other therapeutic agents are playing important roles in
cancer treatment; however, the severe drug resistance and side-effects often
limit the application of chemotherapy. Nano-drug delivery system could
enhance the drug efficacy and reduce the adverse effect by targeted delivery
of drugs to cancer cells. Protein can be a drug delivery vector with the
best biocompatibility in drug delivery. By the conjugation of nanobody,
anticancer drugs demonstrated active targeting to the cancer cells.
Moreover, proteins selves can be used as therapeutic agents. In this case,
proper delivery systems are crucial for protecting proteins from degradation
and maintaining their functions.
References
- Yangzhong Liu, et al. Angew. Chem. Int. Ed., 2021, 60(17), 9480-9488
- Yangzhong Liu, et al. Theranostics, 2021, 11(11):5418-5429
- Yangzhong Liu, et al. Inorg. Chem., 2021, 60, 14515−14519
- Yangzhong Liu, et al. J. Inorg. Biochem. 2021, 223, 111553
- Yangzhong Liu, et al. Chem. Commun., 2020, 56, 9344-9347
- Yangzhong Liu, et al. ACS Appl. Mater. Interfaces, 2020, 12(16), 18309-18318
- Yangzhong Liu, et al. Chem. Eur. J., 2020, 26(33), 7442-745
- Yangzhong Liu, et al. Chem. Sci., 2019, 10, 9721-9728
- Yangzhong Liu, et al. Chem. Commun., 2019, 55, 5175-5178
- Yangzhong Liu, et al. ACS Appl. Mater. Interfaces, 2019, 11, 3645-3653
Biography
Prof. Yangzhong Liu obtained his Master degree in University of
Science and Technology of China (USTC) in 1992. After working at USTC as a
Lecturer, he perused graduate study at University of Bergen in Norway from
1998 in Professor Einar Sletten’s group, and obtained Ph. D. degree in 2002.
He pursued three years postdoctoral research at University of California
from 2002 -2005 at Davis, working with Professor Gerd La Mar on the
paramagnetic protein NMR. He moved to Rensselaer Polytechnic Institute and
worked on multidimensional NMR on 13C/15N isotope labeled proteins with
Professor Chunyu Wang. He returned to the Department of Chemistry at USTC in
2006.
Professor Liu’s research interests are in the broad area of
bioinorganic chemistry and specifically in the mechanistic investigation and
design/delivery of metallo-drugs. He has published more than 100 papers,
including Nat Commun, J Am Chem Soc, Angew Chem Int Ed, Chem Sci, Chem Comm.
He received the award of “Hundred Talents Project” of the Chinese Academy of
Science.
Info
Department of Chemistry, University of Science and Technology of China
Email: liuyz@ustc.edu.cn
Christian G. Hartinger
Professor
University of Auckland
Biology-inspired Ligands and their Metal-based Anticancer Agents
Abstract
Organometallic compounds are emerging as possible new additions to the
toolbox of oncologists and our understanding about their behavior in
biological systems increasingly improves.1 Several compound classes with
interesting modes of action, which are tunable through selection of the
ligands and the metal center, have been reported. For a large majority of
the organometallic anticancer agents, the mode of action is crucially
dependent on covalent interactions with biological target molecules.
We often use bioactive ligands in our efforts to develop new
anticancer
organometallics and coordinate them to metal centers to create multimodal
anticancer agents with ideally synergistic activity between the ligand and
the metal center. Such approaches have led to compounds with significant
anticancer activity in vitro and in vivo.2 In this presentation, I will
focus on ligands featuring a bidentate coordination motif inspired by nature
and their organometallic complexes studied in my group. We have recently
used hydroxypyrones, hydroxyquinolines, oxicams and related structures to
introduce novel functionality in anticancer organometallics.3-6 For these
compounds, we have observed surprising reactions either during the synthesis
or in presence of biomolecules.3 These studies will be complemented with
recent data of relevance to the modes of action of these novel anticancer
agents obtained with a variety of biophysical methods.
References
- Nazarov, A. A.; Hartinger, C. G.; Dyson, P. J., J. Organomet. Chem. 2014, 751, 251-260.
- Meier, S. M.; Kreutz, D.; Winter, L.; Klose, M. H. M.; Cseh, K.; Weiss, T.; Bileck, A.; Alte, B.; Mader, J. C.; Jana, S.; Chatterjee, A.; Bhattacharyya, A.; Hejl, M.; Jakupec, M. A.; Heffeter, P.; Berger, W.; Hartinger, C. G.; Keppler, B. K.; Wiche, G.; Gerner, C., Angew. Chem., Int. Ed. Engl. 2017, 56, 8267-8271.
- Kubanik, M.; Lam, N. Y. S.; Holtkamp, H. U.; Sohnel, T.; Anderson, R. F.; Jamieson, S. M. F.; Hartinger, C. G., Chem. Commun. 2018, 54, 992-995.
- Kurzwernhart, A.; Kandioller, W.; Bartel, C.; Bächler, S.; Trondl, R.; Mühlgassner, G.; Jakupec, M. A.; Arion, V. B.; Marko, D.; Keppler, B. K.; Hartinger, C. G., Chem. Commun. 2012, 48, 4839-4841.
- Małecka, M.; Skoczyńska, A.; Goodman, D. M.; Hartinger, C. G.; Budzisz, E., Coord. Chem. Rev. 2021, 436, 213849.
- Ashraf, A.; Aman, F.; Movassaghi, S.; Zafar, A.; Kubanik, M.; Siddiqui, W. A.; Reynisson, J.; Söhnel, T.; Jamieson, S. M. F.; Hanif, M.; Hartinger, C. G.; Organometallics 2019, 38(2), 361-374.
- Tremlett, W. D. J.; Goodman, D. M.; Steel, T. R.; Kumar, S.; Wieczorek-Blauz, A. Walsh, F. P.; Sullivan, M. P.; Hanif, M.; Hartinger, C. G., Coord. Chem. Rev. 2021, 213950.
Biography
Prof. Christian Hartinger was born in 1974 in Gmünd, Austria. He received a
MSc degree in Chemistry in 1999 from the University of Vienna from which he
also obtained a Ph.D. in Chemistry in 2001 (supervisor: Professor Bernhard
K. Keppler). He received a Schrödinger Fellowship in 2006 to work at the
EPFL in Switzerland with Prof. Paul J. Dyson and returned to Vienna in 2009
to finish his habilitation. Prof. Hartinger was appointed at the University
of Auckland in 2011 where he was promoted to professor in 2016. He is
currently the secretary of the Society of Biological Inorganic Chemistry
(SBIC).
Prof. Hartinger has published more than 230 peer-reviewed
papers in journals such as Angew Chem, Chem Sci, Chem Rev, Coord Chem Rev, J
Med Chem, Chem Comm, Inorg Chem, etc. His papers have been cited over 15400
times, his Scopus h-index is 69, and he is a regular plenary and keynote
speaker at conferences. Prof. Hartinger is the recipient of many national
and international awards including the 2011 Carl-Duisberg-Memorial Prize
(German Chemical Society), the 2016 Society of Biological Inorganic
Chemistry Early Career Award, the 2016 New Zealand Institute of Chemistry
Maurice Wilkins Centre Prize, the 2017 New Zealand Association of Scientists
Beatrice Hill Tinsley Medal and the 2019 Morrison Medal of the Australian
and New Zealand Society for Mass Spectrometry. In 2015 he was a Fellow of
the New Zealand Centre at Beijing University, in 2017 a Hood Fellow
(University of Cambridge, UK) and in 2021 he was elected a Fellow of the
Royal Society of New Zealand.
Info
School of Chemical Sciences, University of Auckland, 23 Symonds Street,
Auckland 1010, New Zealand
Email: c.hartinger@auckland.ac.nz
Zhen-Feng Chen
Professor
Guangxi Normal University
Metal-base Anticancer Agents Basing on New Design Strategy
Abstract
We give rise a thinking of using the coordination regulating effect of
Chinese medicine active ingredients and metal active centre to design
metal-based drugs, and gave rise a new mode to develop metal-based
anticancer agents. Based on the previous research, we carried out new
exploration by utilization of new strategies, such as targeting tublin,
Par-4, EMT relative pathway, glucose metabolism, CDT, and ICD effect. We
synthesized a series of antitumor metal complexes of traditional Chinese
medicines active ingredient alkaloids, oxoaporphine, quinolone and
isoquinoline as well as their derivatives. We have obtained a series of
TCMAI-metal complexes with high in vivo anticancer activity and good in vivo
safety, which provide the possibility to overcome the resistance of
metal-based antitumor drug.
Financial support by the NNSF of China (No.22077022) and NSF
of Guangxi Province of China (No.AD17129007) is gratefully acknowledged.
References
- Z.-F. Chen, H. Liang, et al. Angew. Chem. Int. Ed., 2022, e202208570.
- H. Liang, Z.-F. Chen, et al. J. Med. Chem., 2022, 65, 5134.
- H. Liang, Z.-F. Chen, et al. Eur. J. Med. Chem., 2022, 2022, 231, 114141.
- H. Liang, Z.-F. Chen, et al. Eur. J. Med. Chem., 2022, 236, 114312.
- H. Liang, Z.-F. Chen, et al. Inorg. Chem. Frontiers, 2021, 8, 2225.
- H. Liang, Z.-F. Chen, et al. Eur. J. Med. Chem., 2021, 223, 113636.
Biography
Prof. Chen received his Ph.D. in Inorganic Chemistry from Nanjing
University of China in 2001. Then he worked in Guangxi Normal University of
China as an associate professor. In 2003, he became a professor with a
research focus on medicinal chemistry. In 2004, he was the owner of Program
for New Century Excellent Talents in University of Chinese Ministry of
Education. In 2011, he became the Bagui Scholar of Guangxi Zhuang Autonomous
Region in China. In 2012, he was approved as the Leader of Innovation Team
of Ministry of Education of China. In 2015, he was the Owner of Program for
National Hundred, Thousand and Ten Thousand Talent and National outstanding
contribution and experts of China. In 2016, he was approved to receive the
State Council special allowance. Currently, he is Executive Vice Dean of
State Key Laboratory of State Key Laboratory for Chemistry and Molecular
Engineering of Medicinal Resources at Guangxi Normal University of China. He
has completed five NNSF of China, one 973 Project and two Innovation Team
Project of the Ministry of Education of China and published more about 230
SCI papers in peer-reviewed journals, such as Angew. Chem. Int. Ed., J. Med.
Chem., Eur. J. Med. Chem., Chem. Commun., J. Bio. Chem.; one book chapter,
and is the inventor of 56 authorized China patents. Dr. Chen’s major
research interest is drug discovery in the fields of traditional Chinese
medicine active ingredients metal-based anticancer agents.
Info
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Key Laboratory for Chemistry and Molecular Engineering
of Medicinal Resources (Ministry of Education of China), Collaborative
Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University
Email: chenzf@gxnu.edu.cn
Gilles Gasser
Professor
PSL University
Metal Complexes as Diagnostics and Therapeutics
Abstract
Metal complexes are currently playing a tremendous role in medicine.1 For
example, the platinum complex cisplatin and its derivatives oxaliplatin and
carboplatin are employed in more than 50% of the treatment regimes for
patients suffering from cancer! Over the last years, our research group
focused its attention on the development of novel metal complexes as imaging
and therapeutic agents against cancer and parasitic diseases.2-9 During this
talk, we will present our latest results, including in vivo results, on
these topics.
References
- Boros, E.; Dyson, P. J.; Gasser , G. Classification of Metal-based Drugs According to Their Mechanisms of Action. Chem 2020, 6, 41-60.
- Brandt, M.; Cardinale, J.; Aulsebrook, M. L.; Gasser, G.; Mindt, T. L. An Overview on PET Radiochemistry: Part 2 - Radiometals J. Nucl. Med. 2018, 59, 1500-1506.
- Gourdon, L.; Cariou, K.; Gasser, G. Phototherapeutic anticancer strategies with first-row transition metal complexes: a critical review. Chem. Soc. Rev. 2022, 51, 1167-1195.
- Heinemann, F. W.; Karges, J.; Gasser , G. Critical Overview of the Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-Photon and Two-Photon Photodynamic Therapy. Acc. Chem. Res. 2017, 50, 2727-2736
- Martínez-Alonso, M.; Gasser, G. Ruthenium polypyridyl complex-containing bioconjugates. Coord. Chem. Rev. 2021, 434, 213736.
- Notaro, A.; Gasser , G. Monomeric and Dimeric Coordinatively Saturated and Substitutionally Inert Ru(II) Polypyridyl Complexes as Anticancer Drug Candidates. Chem. Soc. Rev. 2017, 46, 7317-7337.
- Ong, Y. C.; Roy, S.; Andrews, P. C.; Gasser, G. Metal Compounds against Neglected Tropical Diseases. Chem. Rev. 2019, 119, 730-796.
- Patra, M.; Gasser , G. The Medicinal Chemistry of Ferrocene and its Derivatives. Nature Rev. Chem. 2017, 1, 0066, and references therein.
- Patra, M.; Zarschler, K.; Pietzsch, H.-J.; Stephan, H.; Gasser, G. New insights into the pretargeting approach to image and treat tumours. Chem. Soc. Rev. 2016, 45, 6415-6431.
Biography
Prof. Gilles Gasser was born in the French-speaking part of Switzerland in
1976. After completing his MSc. in Chemistry at the University of Neuchâtel
in 2000, he crossed the “Swiss-German border” to work for one year, as a
research chemist, at the multinational agro-pharmaceutical company Lonza Ltd
(Visp, Switzerland) in the Research and Development Division. There, he
developed more economical syntheses of drugs for industry. Thereafter,
Gilles decided to move back to Neuchâtel to undertake a PhD thesis in
supramolecular/coordination chemistry with Prof. Helen Stoeckli-Evans
(2001-2004). In collaboration with Dr. Jim Tucker from the University of
Exeter (now at the University of Birmingham), he developed new ferrocenyl
ligands capable of recognising the presence of biological molecules (amino
acids, urea and barbiturate derivatives) and metallic cations by
electrochemistry. From 2004-2007, endowed with a Swiss National Science
Foundation (SNSF) grant for prospective researchers, Gilles “crossed the
oceans” to carry out a post-doc on bioinorganic chemistry with Prof. Leone
Spiccia (Monash University, Melbourne, Australia). In collaboration with
Prof. Alan M. Bond, he prepared metal complexes which can specifically sense
the presence of DNA bases using electrochemistry. It is also in Australia
that Gilles worked for the first time with the fascinating DNA analogue
Peptide Nucleic Acid (PNA) and their metal derivatives. In 2007, Gilles was
awarded an Alexander von Humboldt Research Fellowship that he took at the
Ruhr-University Bochum (Germany) in the group of Prof. Nils Metzler-Nolte
(2007-2009). There, he notably worked on the preparation and bioevaluation
of new metal-containing PNA bioconjugates for pharmaceutical and biosensing
purposes. At the beginning of 2010, Gilles was given the opportunity to come
back to Switzerland to start his independent research at the Institute of
Inorganic Chemistry (now Department of Chemistry) of the University in
Zurich as a SNSF Ambizione fellow. A year later, in March 2011, Gilles
became an assistant professor at the same institution endowed with a
non-tenure track SNSF professorship. Gilles stayed about 5 years in Zurich,
working mainly on the field of Photodynamic Therapy (PDT) and
bioorganometallic chemistry. In October 2016, Gilles joined Chimie ParisTech
from the newly created Paris Sciences & Lettres (PSL) University thanks,
among others, to an ERC Consolidator Grant and a PSL Chair of Excellence
Program Grant. In Paris, the current research interests of Gilles and his
group cover various fields of inorganic chemical biology and medicinal
inorganic chemistry, thereby focusing in using metal complexes to modulate
the properties of biomolecules.
Gilles was the recipient of several fellowships and awards
including the Alfred Werner Award from the Swiss Chemical Society, an ERC
Consolidator Grant, the European BioInorganic Chemistry (EuroBIC) medal and
the Pierre Fabre Award for therapeutic innovation from the French Société de
Chimie Thérapeutique. Gilles is an associate editor of Metallomics and is a
Fellow of the Royal Society of Chemistry.
Info
Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and
Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris,
France
Hui Chao
Professor
Sun Yat-Sen University
Metal Complexes as Two-Photon PDT Agents
Abstract
Cancer has long been one of the world’s deadliest diseases. Photodynamic
therapy (PDT) is a noninvasive medical technique, which has received
increasing attention over the last years to treat certain types of cancer.
However, the current clinically-used PDT agents are plagued by a number of
issues including a general poor water solubility and slow clearance from the
body, weak photo-stability, and the necessity for irradiation by a high
energy one-photon (OP) laser beam. In order to tackle these drawbacks,
two-photon PDT (TP-PDT) agents have emerged over the recent years as
attractive alternatives to the currently approved photosensitizers. Recently
we have focused on Ir(III) polypyridyl complexes which were found to be
excellent candidates owing to their attractive photophysical properties
(i.e. high water solubility, large 2, high 3O2 production, long luminescence
lifetime, and excellent chemical- and photo-stability). Our results
indicated that these complexes may be an efficient two-photon PDT candidate.
References
- Zhao, X.; Liu, J.; Fan, J.; Chao, H.; Peng, X. Chem. Soc. Rev., 2021, 50, 4185.
- Huang, H.; Banerjee, S.; Qiu, K.; Zhang, P.; Blacque, O.; Malcomson, T.; Paterson, M. J.; Clarkson, G. J.; Staniforth, M.; Stavros, V. G.; Gasser, G.; Chao, H.; Sadler, P. J. Nat. Chem., 2019, 11, 1041.
- Kuang, S.; Wei, F.; Karges, J.; Ke, L.; Xiong, K.; Liao, X.; Gasser, G.; Ji, L.; Chao, H. J. Am. Chem. Soc., 2022, 144, 4091.
- Ke, L.; Wei, F.; Xie, L.; Karges, J.; Chen, Y.; Ji, L.; Chao, H. Angew. Chem. Int. Ed., 2022, 61, e202205429.
- Kuang, S.; Sun, L.; Zhang, X.; Liao, X.; Rees, T. W.; Zeng, L..; Chen, Y.; Zhang, X.; Ji, L.; Chao, H.; Angew. Chem. Int. Ed., 2020, 59, 20697.
- Kuang, S.; Liao, X.; Zhang, X.; Rees, T. W.; Guan, R.; Xiong, K.; Chen, Y.; Ji, L.; Chao, H.; Angew. Chem. Int. Ed., 2020, 59, 3315.
Biography
Hui Chao is the full professor in the School of Chemistry at Sun Yat-Sen
University. He received his PhD from Sun Yat-Sen University in 2000 with
Prof. Liangnian Ji. During 2000-2003, he attended Hong Kong University of
Science and Technology every year as a short-term visiting scholar. In
2004-2005, he conducted postdoctoral work at Texas A&M University with Prof.
F. Albert Cotton. He has published over 230 research papers in refereed
journals and 8 book chapters. His current research interest is focused on
metal-based anticancer drugs and bioimaging agents.
Info
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of
Chemistry, Sun Yat-Sen University
Email: ceschh@mail.sysu.edu.cn
Walter Berger
Professor
Medical University Vienna
The (pre)clinical ruthenium compound BOLD-100 targets cancer cell
metabolism
Abstract
Changes in cellular metabolism during malignant transformation links
energetic and epigenetic adaptation with evasion of growth suppression and
cell death resistance. Metabolic alterations in response and resistance to
metal-based anti-cancer therapy are widely unexplored. Here, we combined a
multitude of cell/molecular biological analyses with analytical chemistry
and multi-omics approaches to dissect the metabolic implications of
metal-based chemotherapy. Moreover, we studied metabolic mechanisms
underlying acquired metal-based chemotherapy resistance with the aim to
detect combination therapy targets for resistance circumvention. We focused
on the anticancer ruthenium complex sodium
trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). BOLD-100 is an
ER-stress inducer currently in multicenter clinical phase II assessment in
combination with FOLFOX against gastrointestinal cancers. Major phenotypic
differences in acquired resistance to ruthenium compared to platinum drugs
were identified. Exemplarily, the metabolic fluxes of fatty acid metabolism,
the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation were more
abundant in BOLD-100- (HCTR) compared to oxaliplatin-resistant (HCT/OxR)
HCT116 colon cancer sublines1. Metabolomics and Seahorse analyses identified
BOLD-100 as an anti-Warburg drug depleting parental HCT116 cells of lactate
and pyruvate2. Furthermore, we detected interference of BOLD-100 with
cellular lipid metabolism via regulation of lipid droplets (LD) formation.
Computational network analysis of gene expression and metabolomics data
revealed a clear upregulation of glycolysis in HCTR cells, associated with
autophagy deregulation and creating a vulnerability towards glucose
deprivation by 2-deoxyglucose (2-DG). Moreover, HCTR cells presented a
massively increased LD load based on upregulated de novo fatty acid
synthesis culminating in a hypersensitivity towards lipid metabolism
inhibitors. Exemplarily, the ß-oxidation inhibitor etomoxir efficiently
reduced HCTR cell/tumor growth in vitro and in vivo. Furthermore, 2-DG
treatment reduced LD levels in HCTR cells, indicating dependence of lipid
enrichment on glycolytic activity. Coenzyme A (CoA) is the key metabolite
connecting the TCA cycle with lipid metabolism and, consequently, histone
acetylation. Importantly, BOLD-100 treatment reduced histone acetylation
only in parental but not BOLD-100-resistant HCT116 cells. Consequently, mass
spectrometric and NMR analyses revealed formation of a BOLD-100-CoA
thioester under cell-free conditions, which provides a rational explanation
for the reduced epigenetic acetylation mark. Combination of BOLD-100 with
the CoA-binding compound 4-phenylbutyric acid showed synergistic anticancer
activity in several tested cancer models and reversed BOLD-100 resistance.
Overall, we have identified a strong metabolic activity of BOLD-100 and
present strategies to target BOLD-100 resistance by metabolic interventions.
References
- L. Galvez L et al. Metallomics. 2019, 11(10):1716
- D. Baier et al. Pharmaceutics. 2022, 14(2):238.
Biography
Prof. Walter Berger was born in Reichraming, Austria on October 19th, 1963.
He received a PhD in cell biology from Vienna University in 1993. After a 5
years’ period in product and project management with Hoechst/Austria
Company, he changed to a research position at the Institute of Cancer
Research at Vienna University. After a postdoc stay in Cambridge/UK, he
became Associate professor at Medical University Vienna.
Currently, Walter Berger is Chair of Applied and Experimental
Oncology and Deputy Head of the Center of Cancer Research at the Medical
University of Vienna, Austria. He is, together with Bernhard Keppler,
Department of Inorganic Chemistry at University of Vienna, co-founder of the
interuniversity research platform for Experimental Cancer Therapy
Development and of the spin-off company P4 Therapeutics. In his scientific
work, he focusses on the translation of molecular and cellular research
approaches towards clinical oncology by developing novel therapy targets but
also drug formulations. In several research networks, he is connected both
with clinical oncologists, immunologists, and pathologists, but also
synthetic and analytical chemists. A major focus lies on the utilisation of
novel anticancer drug candidates for tumor specific drug activation and
targeted therapy approaches against therapy-resistant malignancies like
thoracic cancers and pediatric as well as adult brain tumors. Walter Berger
was awarded with several prizes in the field of translational cancer
research. He is author of about 310 SCI publications (including Cell, Cancer
Cell, Clinical Cancer Research, Angewandte Chemie Int Ed, Chemical Reviews)
and holds currently a Scopus H-index of 60.
Info
Center for Cancer Research, Medical University Vienna, Austria
Fuyi Wang
Professor
Chinese Academy of Sciences
G-quadruplex inducer/stabilizer pyridostatin promotes cytotoxicity of a
transplatinum complex via reducing PC4-mediated repair of platinated DNA
Abstract
Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and
stabilizer, yet its target genes have remained unclear [1]. In this work,
combining mass spectrometric proteomics strategy with bioinformatics
analysis, we revealed that PDS significantly downregulated 22 proteins, of
which the genes contain rich G4 potential sequences, in HeLa cancer cells,
meanwhile upregulating 16 proteins remarkably. The PDS-regulated proteins
appeared to work synergistically to activate cyclin and cell cycle
regulation, and to restrain the inhibition of ARE-mediated mRNA decay
pathway, suggesting that PDS itself is not a potential anticancer agent, at
least towards HeLa cancer. Importantly, among the PDS targeted genes, SUB1,
which expresses the human positive cofactor and DNA lesion sensor PC4 [2],
was down-regulated by 4.76-fold. Further studies demonstrated that the
downregulation of PC4 dramatically promoted the cytotoxicity of
trans-[PtCl2(NH3)(thiazole)] towards HeLa cells to a similar level to that
of cisplatin, contributable to retarding the repair of 1,3-trans-platinated
DNA lesion mediated by PC4. These findings not only provide new insights
into better understanding on the biological functions of PDS, but also
implicate a strategy for the rational design of novel multi-targeting
platinum anticancer drugs via conjugation of PDS as a ligand to the
coordination scaffold of transplatin for battling drug resistance to
cisplatin.
Figure 1. The G-quadruplex inducer/stabilizer pyridostatin
(PDS) downregulated the human positive cofactor PC4, significantly promoting
the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] (Trans-PtTz) towards HeLa
cells, contributable to reduction in PC4-mediated repair of transplatinated
DNA lesion.
Keywords: Pyridostatin; G-Quadruplex; Chemical Proteomics;
Platinum;
References
- Rodriguez, R.; Muller, S.; Yeoman, J. A. ; Trentesaux, C.; Riou, J. F.; Balasubramanian, S. J. Am. Chem. Soc., 2008, 130, 15758.
- Du. Z. F.; Luo, Q.; Yang, L. P.; Bing, T.; Li, X. C.; Guo, W.; Wu, K.; Zhao, Y.; Xiong, S. X.; Shangguan, D. H.; Wang, F. Y. J. Am. Chem. Soc., 2014, 136, 2948.
Biography
Dr. Fuyi Wang received his PhD degree at Wuhan University in 1999, and then
spent seven years as a research associate/fellow in inorganic biochemistry
and molecular pharmacology at the University of Edinburgh, the United
Kingdom. In 2007 he was awarded with the Overseas Talent Program Award of
the Chinese Academy of Sciences and appointed as a full professor in
chemistry at the Institute of Chemistry, the Chinese Academy of Sciences,
where he was appointed as the director of the National Centre for Mass
Spectrometry in Beijing in 2015. Dr. Wang is also a professor at the College
of Chemical Science, the University of Chinese Academy of Sciences. His
research interests are centered on mass spectrometry and its applications in
chemical biology and drug discovery. He has been a principal investigator
for more than 10 national key research projects, and published so far more
than 160 SCI-indexed papers in high impact journals, such as JACS, Angew.
Chem., Chem. Sci. and Nucleic Acid Res., and was granted with 9 Chinese
patents and 5 International patents.
Info
Institute of Chemistry, Chinese Academy of Sciences
College of Chemical Science, University of Chinese Academy of
Sciences
Email: fuyi.wang@iccas.ac.cn