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Synthesis of adamantane-monoterpene conjugates with 1,3,4-thiadiazol-2(3H)-imine linker and evaluation of their inhibitory activity against TDP1

Munkuev, Aldar A.; Zakharenko, Alexandra L.; Kornienko, Tatyana E.; Dyrkheeva, Nadezhda S.; Ilina, Ekaterina S.; Suslov, Evgeniy V.; Issa, Fatima; Achara, Chigozie; Reynisson, Jóhannes; Volcho, Konstantin P.; Salakhutdinov, Nariman F.; Lavrik, Olga I.

Authors

Aldar A. Munkuev

Alexandra L. Zakharenko

Tatyana E. Kornienko

Nadezhda S. Dyrkheeva

Ekaterina S. Ilina

Evgeniy V. Suslov

Fatima Issa

Chigozie Achara

Konstantin P. Volcho

Nariman F. Salakhutdinov

Olga I. Lavrik



Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme that can reduce the efficacy of some anticancer drugs targeting topoisomerase 1 (TOP1) making it a promising target for antitumor therapy when combined with TOP1 poisons. Here we describe the synthesis of a number of adamantane-monoterpene conjugates 20a–g and 21a–g connected through a 1,3,4-thiadiazol-2(3H)-imine linker, where acyclic, monocyclic, and bicyclic structural types of monoterpenes were used. All the synthesized compounds demonstrated activity against TDP1 in micromolar range, with the most potent inhibitor being compound 21a (IC50 1.2 μM). The cytotoxic effects of these compounds determined in the HEK293A and HeLa cell lines were low to moderate. These findings imply that such compounds are promising for further development of new TDP1 inhibitors with favorable physicochemical properties.

Citation

Munkuev, A. A., Zakharenko, A. L., Kornienko, T. E., Dyrkheeva, N. S., Ilina, E. S., Suslov, E. V., …Lavrik, O. I. (2024). Synthesis of adamantane-monoterpene conjugates with 1,3,4-thiadiazol-2(3H)-imine linker and evaluation of their inhibitory activity against TDP1. Medicinal Chemistry Research, 33(2), 324-335. https://doi.org/10.1007/s00044-023-03184-x

Journal Article Type Article
Acceptance Date Dec 18, 2023
Online Publication Date Jan 12, 2024
Publication Date 2024-02
Deposit Date Apr 23, 2024
Journal Medicinal Chemistry Research
Print ISSN 1054-2523
Electronic ISSN 1554-8120
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 33
Issue 2
Pages 324-335
DOI https://doi.org/10.1007/s00044-023-03184-x
Keywords Organic Chemistry; General Pharmacology, Toxicology and Pharmaceutics
Additional Information Received: 15 September 2023; Accepted: 18 December 2023; First Online: 12 January 2024; : ; : The authors declare no conflict of interest.