Novel derivatives of deoxycholic acid bearing aliphatic or cyclic diamine moieties at the C-3 position: Synthesis and evaluation of anti-proliferative activity

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3755-3759. doi: 10.1016/j.bmcl.2017.06.072.

Irina I Popadyuk ¹, Andrey V Markov ², Valeriya O Babich ³, Oksana V Salomatina ⁴, Evgeniya B Logashenko ⁵, Marina A Zenkova ⁶, Nariman F Salakhutdinov ⁷

Affiliations

1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch Russian Academy of Sciences, 9, Lavrent'ev ave., Novosibirsk 630090, Russian Federation. Electronic address: popadyuk@nioch.nsc.ru.
2 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch Russian Academy of Sciences, 8, Lavrent'ev ave., Novosibirsk 630090, Russian Federation. Electronic address: andmrkv@gmail.com.
3 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch Russian Academy of Sciences, 8, Lavrent'ev ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, 2, Pirogova Str., Novosibirsk 630090, Russian Federation. Electronic address: vlgrps@gmail.com.
4 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch Russian Academy of Sciences, 9, Lavrent'ev ave., Novosibirsk 630090, Russian Federation. Electronic address: ana@nioch.nsc.ru.
5 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch Russian Academy of Sciences, 8, Lavrent'ev ave., Novosibirsk 630090, Russian Federation. Electronic address: evg_log@niboch.nsc.ru.
6 Institute of Chemical Biology and Fundamental Medicine, Siberian Branch Russian Academy of Sciences, 8, Lavrent'ev ave., Novosibirsk 630090, Russian Federation. Electronic address: marzen@niboch.nsc.ru.
7 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch Russian Academy of Sciences, 9, Lavrent'ev ave., Novosibirsk 630090, Russian Federation; Novosibirsk State University, 2, Pirogova Str., Novosibirsk 630090, Russian Federation. Electronic address: anvar@nioch.nsc.ru.

PMID: 28688958 DOI: 10.1016/j.bmcl.2017.06.072

Abstract

A new library of deoxycholic acid derivatives bearing nitrogen-containing moieties at the C-3 position was synthesised from epoxy derivative 1 via an epoxide ring-opening reaction promoted by aliphatic or cyclic diamines and fully characterised by NMR and mass-spectroscopy. The synthesised compounds were screened for cytotoxicity against four human tumour cell lines. The results showed that some of the novel diamine-bearing derivatives displayed improved anti-proliferative activities over the parent compound DCA. Among them, a 1-methylpiperazine containing compound (6) showed promising activity and the highest selectivity against tumour cells of enterohepatic origin (HepG2: IC₅₀=3.6µM, SI=9.0; HuTu-80: IC₅₀=4.6µM, SI=6.9) and was identified as a lead molecule.

Keywords

Anti-proliferative activity; Cytotoxicity; Deoxycholic acid derivatives; Diamines; Epoxides.

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