Dehydroabietylamine Ureas and Thioureas as Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Enhance the Antitumor Effect of Temozolomide on Glioblastoma Cells

Kseniya Kovaleva; Olga Oleshko; Evgeniya Mamontova; Olga Yarovaya; Olga Zakharova; Alexandra Zakharenko; Alena Kononova; Nadezhda Dyrkheeva; Sergey Cheresiz; Andrey Pokrovsky; Olga Lavrik; Nariman Salakhutdinov

doi:10.1021/acs.jnatprod.8b01095

Dehydroabietylamine Ureas and Thioureas as Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Enhance the Antitumor Effect of Temozolomide on Glioblastoma Cells

J Nat Prod. 2019 Sep 27;82(9):2443-2450. doi: 10.1021/acs.jnatprod.8b01095. Epub 2019 Aug 20.

Authors

Kseniya Kovaleva^{1

2}, Olga Oleshko², Evgeniya Mamontova³, Olga Yarovaya^{1

2}, Olga Zakharova³, Alexandra Zakharenko³, Alena Kononova², Nadezhda Dyrkheeva³, Sergey Cheresiz^{2

4}, Andrey Pokrovsky², Olga Lavrik^{2

3}, Nariman Salakhutdinov^{1

2}

Affiliations

¹ N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences , Novosibirsk , 630090 , Russian Federation.
² Novosibirsk State University , Novosibirsk , 630090 , Russian Federation.
³ Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences , Novosibirsk , 630090 , Russian Federation.
⁴ State Scientific Research Institute of Physiology and Basic Medicine , P.O. Box 237, Novosibirsk , 630117 , Russian Federation.

PMID: 31430155
DOI: 10.1021/acs.jnatprod.8b01095

Abstract

A new class of tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors was found among resin acid derivatives. Several novel ureas and thioureas derived from dehydroabietylamine were synthesized and tested for TDP1 inhibition. The synthesized compounds showed IC₅₀ values in the range of 0.1 to 3.7 μM and demonstrated low cytotoxicity against the human tumor cell lines U-937, U-87MG, MDA-MB, SK-Mel8, A-549, MCF7, T98G, and SNB19. Several compounds showed enhancement of the cytotoxic activity of the alkylating agent temozolomide, which is used as a first line therapy against glioblastoma (GBM), in the GBM cell lines U-87MG and SNB19.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Alkylating / therapeutic use*
Brain Neoplasms / pathology*
Cell Line, Tumor
DNA, Neoplasm / chemistry
DNA, Neoplasm / drug effects*
Drug Synergism
Glioblastoma / pathology*
Humans
Phosphodiesterase Inhibitors / chemistry
Phosphodiesterase Inhibitors / pharmacology*
Temozolomide / therapeutic use*
Thiourea / chemistry*
Tyrosine / chemistry*
Urea / chemistry*

Substances

Antineoplastic Agents, Alkylating
DNA, Neoplasm
Phosphodiesterase Inhibitors
Tyrosine
Urea
Thiourea
Temozolomide