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
ISSN: 1420-3049

Output data

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

Tags

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

Authors

Munkuev A.A. ¹ , Dyrkheeva N.S. ² , Kornienko T.E. ² , Ilina E.S. ² , Ivankin D.I. ¹ , Suslov E.V. ¹ , Korchagina D.V. ¹ , Gatilov Y.V. ¹ , Zakharenko A.L. ² , Malakhova A.A. ^2,3 , Reynisson J. ⁴ , Volcho K.P. ¹ , Salakhutdinov N.F. ¹ , Lavrik O.I. ^2,5

Affiliations

1	N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
2	Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
3	Federal Research Centre Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
4	School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK;
5	Department of Physical and Chemical Biology and Biotechnology, Altai State University, Pr. Lenina 61, 656049 Barnaul, Russia

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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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. 3374 . DOI: 10.3390/molecules27113374 WOS Scopus OpenAlex

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

DB	Citing
Scopus	10
Web of science	11
OpenAlex	14