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

Molecules

Olga I. Lavrik¹  Alexandra L. Zakharenko¹  Ekaterina S. Ilina¹  Tatyana E. Kornienko¹  Anastasia A. Malakhova¹  Nadezhda S. Dyrkheeva¹  Yuriy V. Gatilov²  Nariman F. Salakhutdinov²  Aldar A. Munkuev²  Dmitry I. Ivankin²  Konstantin P. Volcho²  Dina V. Korchagina²  Evgeniy V. Suslov²  Jóhannes Reynisson³ 

[1] Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia;N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia;School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK;

关键词: tyrosyl-DNA phosphodiesterase 1;    adamantane;    monoterpene;    TDP1 inhibitors;    1,2,4-triazole;    1,3,4-thiadiazole;   

DOI  :  10.3390/molecules27113374

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown