Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan
Aldar A. Munkuev,
Nadezhda S. Dyrkheeva,
Tatyana E. Kornienko,
Ekaterina S. Ilina,
Dmitry I. Ivankin,
Evgeniy V. Suslov,
Dina V. Korchagina,
Yuriy V. Gatilov,
Alexandra L. Zakharenko,
Anastasia A. Malakhova,
Jóhannes Reynisson,
Konstantin P. Volcho,
Nariman F. Salakhutdinov,
Olga I. Lavrik
Affiliations
Aldar A. Munkuev
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Nadezhda S. Dyrkheeva
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Tatyana E. Kornienko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Ekaterina S. Ilina
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Dmitry I. Ivankin
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Evgeniy V. Suslov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Dina V. Korchagina
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Yuriy V. Gatilov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Alexandra L. Zakharenko
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Anastasia A. Malakhova
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Jóhannes Reynisson
School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK
Konstantin P. Volcho
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Nariman F. Salakhutdinov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia
Olga I. Lavrik
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, 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.
