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A n n u a l C o n g r e s s o n
Medicinal Chemistry,
Pharmacology and toxicology
Journal of Organic & Inorganic Chemistry
ISSN: 2472-1123
J u l y 3 0 - 3 1 , 2 0 1 8
Am s t e r d a m , N e t h e r l a n d s
Medchem & Toxicology 2018
Page 20
T
he cytotoxic effects of chemotherapy and radiation that are clinically used
to treat malignances are directly related to their propensity to generate DNA
damage. The capacity of cancer cells to recognize DNA damage and initiate DNA
repair is a key mechanism for therapeutic resistance to chemotherapy. Therefore,
the targeting of DNA repair enzymes can be used as a strategy to potentiate
the cytotoxicity of the currently available DNA damaging agents toward cancer
cells. PARP1 (poly ADP ribose polymerase 1, the enzyme involved in DNA repair)
inhibitors such asOlaparib, Rucaparib andNiraparib are in clinical use already. New
and very promising target for antitumor therapy is tyrosyl-DNA phosphodiesterase
1 (Tdp1). It plays a key role in the removal of DNA damage resulting from inhibition
of topoisomerase 1 (Topo1) with camptothecin and its clinical derivatives
irinotecan and topotecan. Furthermore, Tdp1 is known to be capable of removing
the DNA damage induced by other anticancer drugs commonly used in clinical
practice. To date, a number of Tdp1 inhibitors of various types including dual
Tdp1/Topo1 inhibitors are known. A set of very potent Tdp1 inhibitors was found
by us among natural products derivatives. We designed new inhibitors using
targeted modifications of terpenoids, coumarins, usnic acid and other types of
natural products. Moreover, we found that benzopentathiepine derivatives are very
effective inhibitors of Tdp1. Important that the ability of the inhibitors used in non-
toxic concentration to enhance the cytotoxicity of camptothecin and topotecan,
the established topoisomerase 1 poison, was demonstrated. Thus, we discovered
of new original Tdp1 inhibitors, effectively inhibiting DNA repair in tumour cells for
use as the components of complex anticancer drugs.
Biography
Konstantin Volcho received his PhD in 1997 from Novosibirsk
State University, Russia. Since that he has been working at
Novosibirsk Institute of Organic Chemistry (Russia) in the
Department of Medicinal Chemistry. He is a Professor of
Russian Academy of Science. His research interests include
Development of Novel Treatments against Nervous System
Disorders, Antivirals and Anticancer Agents, Usually Based on
Natural Products Derivatization. He has published about 150
papers in reputed journals. He is an Inventor in more than 35
issued patents. Three compounds found with his participation
are currently in preclinical studies as anti-Parkinsonian,
analgesic and antidepressant agents.
Volcho@nioch.nsc.ruDNA repair enzymes inhibition as a promising
approach to new anti-cancer drugs
Konstantin Volcho
Novosibirsk Institute of Organic Chemistry, Novosibirsk, Russia
Konstantin Volcho, J Org Inorg Chem 2018, Volume 4
DOI: 10.21767/2472-1123-C3-007