Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments

Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments Научная публикация

Журнал

Anti-Cancer Agents in Medicinal Chemistry
ISSN: 1871-5206 , E-ISSN: 1875-5992

Вых. Данные

Год: 2019, Том: 19, Номер: 4, Страницы: 463-472 Страниц : DOI: 10.2174/1871520619666181207094243

Ключевые слова

Citronellol; esters; terpene; inhibitors; cytotoxicity; molecular modelling; chemical space; 3,7-dimethy loctanol

Авторы

Mozhaitsev Evgcnii S. ¹ , Zakharenko Alexandra L. ² , Suslov Evgeniy, V ¹ , Korchagina Dina, V ¹ , Zakharova Olga D. ² , Vasil'eva Inna A. ² , Chepanova Anna A. ² , Black Ellena ⁴ , Patel Jinal ⁴ , Chand Raina ⁴ , Reynisson Johannes ⁴ , Leung Ivanhoe K. H. ⁴ , Volcho Konstantin P. ^1,3 , Salakhutdinov Nariman F. ^1,3 , Lavrik Olga, I ^2,3

Организации

1	(Данные Web of science) Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, 9 Lavrentiev Ave, Novosibirsk 630090, Russia
2	(Данные Web of science) Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, 8 Lavrentiev Ave, Novosibirsk 630090, Russia
3	(Данные Web of science) Novosibirsk State Univ, 2 Pirogova Str, Novosibirsk 630090, Russia
4	(Данные Web of science) Univ Auckland, Sch Chem Sci, Private Bag 92019,Victoria St West, Auckland 1142, New Zealand

Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDPI inhibitors. Methods: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. Results: 13 Novel ester-based TDPI inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 mu M. Molecular modelling against the 1DP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7-dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug. against the human lung adenocarcinoma cell line A549. Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

Mozhaitsev E.S. , Zakharenko A.L. , Suslov E.V. , Korchagina D.V. , Zakharova O.D. , Vasil'eva I.A. , Chepanova A.A. , Black E. , Patel J. , Chand R. , Reynisson J. , Leung I.K.H. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments
Anti-Cancer Agents in Medicinal Chemistry. 2019. V.19. N4. P.463-472. DOI: 10.2174/1871520619666181207094243 WOS Scopus РИНЦ

Опубликована в печати:

25 июн. 2019 г.

Web of science	WOS:000472726300004
Scopus	2-s2.0-85054071064
РИНЦ	41620510
OpenAlex	W2905151047