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

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.