Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents

Sergey E. Sosonyuk; Anita Peshich; Anastasia V. Tutushkina; Dmitry A. Khlevin; Natalia A. Lozinskaya; Yulia A. Gracheva; Valeria A. Glazunova; Dmitry I. Osolodkin; Marina N. Semenova; Victor V. Semenov; Vladimir A. Palyulin; Marina V. Proskurnina; Alexander A. Shtil; Nikolay S. Zefirov

doi:10.1039/C8OB02915F

Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents†

Sergey E. Sosonyuk,*^a Anita Peshich,^a Anastasia V. Tutushkina,^a Dmitry A. Khlevin,^a Natalia A. Lozinskaya,

^ab Yulia A. Gracheva,^a Valeria A. Glazunova,^c Dmitry I. Osolodkin,

^ade Marina N. Semenova,^f Victor V. Semenov,^g Vladimir A. Palyulin,^ab Marina V. Proskurnina,^ab Alexander A. Shtil^ac and Nikolay S. Zefirov ‡^ab

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* Corresponding authors

^a Department of Chemistry, Lomonosov Moscow State University, 1-3 Leninskie Gory, Moscow, Russia
E-mail: umpolung@yandex.ru
Fax: +7-495-939-02-90

^b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severniy Proezd, Chernogolovka, Moscow Region, Russia

^c Blokhin National Medical Center of Oncology, 24 Kashirskoye Shosse, Moscow, Russia

^d FSBSI “Chumakov FSC R&D IBP RAS”, 8 bd. 1 Poselok Instituta Poliomielita, Poselenie Moskovsky, Moscow 108819, Russia

^e Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow 119991, Russia

^f Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia

^g Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia

Abstract

Mixed simplified structures containing the paclitaxel and eleutherobin pharmacophore moieties were analyzed using molecular docking techniques and synthesized based on adamantane and 8-oxabicyclo[3.2.1]octane scaffolds. The crucial role of substituents’ stereochemistry in biological activity is discussed. At micromolar concentrations the selected analogues interfered with tubulin dynamics in vitro and in a living organism. Furthermore, new compounds were cytotoxic against human tumour cell lines. The simplified eleutherobin analogues may be considered as prototypes of a new class of antitumour agents.

This article is part of the themed collection: Synthetic methodology in OBC

Organic & Biomolecular Chemistry

Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents†

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Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents

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