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

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

Journal

Molecules
, E-ISSN: 1420-3049

Output data

Year: 2022, Volume: 27, Number: 11, Pages: 3374 Pages count : 1 DOI: 10.3390/molecules27113374

Tags

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

Authors

Munkuev Aldar A. ¹ , Dyrkheeva Nadezhda S. ² , Kornienko Tatyana E. ² , Ilina Ekaterina S. ² , Ivankin Dmitry I. ¹ , Suslov Evgeniy V. ¹ , Korchagina Dina V. ¹ , Gatilov Yuriy V. ¹ , Zakharenko Alexandra L. ² , Malakhova Anastasia A. ^2,3 , Reynisson Jóhannes ⁴ , Volcho Konstantin P. ¹ , Salakhutdinov Nariman F. ¹ , Lavrik Olga I. ^2,5

Affiliations

1	N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian Branch of Russian Academy of Sciences
2	Institute of Chemical Biology and Fundamental Medicine SB RAS
3	Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences
4	Keele University
5	Altai State University

Funding (1)

Российский Научный Фонд

19-13-00040

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.

Munkuev A.A. , Dyrkheeva N.S. , Kornienko T.E. , Ilina E.S. , Ivankin D.I. , Suslov E.V. , Korchagina D.V. , Gatilov Y.V. , Zakharenko A.L. , Malakhova A.A. , Reynisson J. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan
Molecules. 2022. V.27. N11. P.3374. DOI: 10.3390/molecules27113374 WOS Scopus РИНЦ

Submitted:	Apr 29, 2022
Published online:	May 24, 2022

Web of science	WOS:000809087000001
Scopus	2-s2.0-85131621603
Elibrary	49149577
OpenAlex	W4281477670