Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones as catalytic inhibitors of human DNA topoisomerase IIα.

08:00 EDT 25th April 2019 | BioPortfolio

Summary of "Structure-guided optimization of 4,6-substituted-1,3,5-triazin-2(1H)-ones as catalytic inhibitors of human DNA topoisomerase IIα."

Human DNA topoisomerases represent one of the key targets of modern chemotherapy. An emerging group of catalytic inhibitors of human DNA topoisomerase IIα comprises a new paradigm directed to circumvent the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. In our previous studies, 4,6-substituted-1,3,5-triazin-2(1H)-ones were discovered as catalytic inhibitors of topo IIα. Here, we report the results of our efforts to optimize several properties of the initial chemical series that did not exhibit cytotoxicity on cancer cell lines. Using an optimized synthetic route, a focused chemical library was designed aimed at further functionalizing substituents at the position 4 of the 1,3,5-triazin-2(1H)-one scaffold to enable additional interactions with the topo IIα ATP binding site. After virtual screening, selected 36 analogues were synthesized and experimentally evaluated for human topo IIα inhibition. The optimized series displayed improved inhibition of topo IIα over the initial series and the catalytic mode of inhibition was confirmed for the selected active compounds. The optimized series also showed cytotoxicity against HepG2 and MCF-7 cell lines and did not induce double-strand breaks, thus displaying a mechanism of action that differs from the topo II poisons on the cellular level. The new series represents a new step in the development of the 4,6-substituted-1,3,5-triazin-2(1H)-one class towards novel efficient anticancer therapies utilizing the catalytic topo IIα inhibition paradigm.


Journal Details

This article was published in the following journal.

Name: European journal of medicinal chemistry
ISSN: 1768-3254
Pages: 330-348


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Medical and Biotech [MESH] Definitions

RNA that has catalytic activity. The catalytic RNA sequence folds to form a complex surface that can function as an enzyme in reactions with itself and other molecules. It may function even in the absence of protein. There are numerous examples of RNA species that are acted upon by catalytic RNA, however the scope of this enzyme class is not limited to a particular type of substrate.

Amidines substituted with a benzene group. Benzamidine and its derivatives are known as peptidase inhibitors.

Biological molecules that possess catalytic activity. They may occur naturally or be synthetically created. Enzymes are usually proteins, however CATALYTIC RNA and CATALYTIC DNA molecules have also been identified.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

ENDOPEPTIDASES which have a cysteine involved in the catalytic process. This group of enzymes is inactivated by CYSTEINE PROTEINASE INHIBITORS such as CYSTATINS and SULFHYDRYL REAGENTS.

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