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.

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.

• 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.