Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan.

Reynisson

doi:10.3390/molecules27113374

Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan.

Reynisson

Authors

Johannes Reynisson j.reynisson@keele.ac.uk

Abstract

Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a-14b and 15a-b showed activity against TDP1 at a low micromolar range with IC50 ~5-6 µM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.

Acceptance Date	May 22, 2022
Publication Date	May 24, 2022
Journal	Molecules
Publisher	MDPI
DOI	https://doi.org/10.3390/molecules27113374
Keywords	tyrosyl-DNA phosphodiesterase 1; adamantane; monoterpene; TDP1 inhibitors; 1,2,4-triazole; 1,3,4-thiadiazole; synergy
Publisher URL	https://www.mdpi.com/1420-3049/27/11/3374