6-(4'-Aryl-1',2',3'-triazolyl)-spirostan-3,5-diols and 6-(4'-Aryl-1',2',3'-triazolyl)-7-hydroxyspirosta-1,4-dien-3-ones: Synthesis and analysis of their cytotoxicity

Maxim E Mironov; Olga S Oleshko; Mikhail A Pokrovskii; Tatyana V Rybalova; Vladislav K Pechurov; Andrey G Pokrovskii; Sergey V Cheresis; Sergey V Mishinov; Vyacheslav V Stupak; Elvira E Shults

doi:10.1016/j.steroids.2019.108460

6-(4'-Aryl-1',2',3'-triazolyl)-spirostan-3,5-diols and 6-(4'-Aryl-1',2',3'-triazolyl)-7-hydroxyspirosta-1,4-dien-3-ones: Synthesis and analysis of their cytotoxicity

Steroids. 2019 Nov:151:108460. doi: 10.1016/j.steroids.2019.108460. Epub 2019 Jul 22.

Affiliations

¹ Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russian Federation; Novosibirsk State University, Pirogova Str. 2, 630090 Novosibirsk, Russian Federation.
² Novosibirsk State University, Pirogova Str. 2, 630090 Novosibirsk, Russian Federation.
³ First Department of Neurosurgery, Ya. L. Tsivian Novosibirsk Research Institute of Traumatology and Orthopaedics, Frunze Str. 17, 630091 Novosibirsk, Russian Federation.
⁴ Laboratory of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentyev Ave, 9, 630090 Novosibirsk, Russian Federation; Novosibirsk State University, Pirogova Str. 2, 630090 Novosibirsk, Russian Federation. Electronic address: schultz@nioch.nsc.ru.

PMID: 31344410
DOI: 10.1016/j.steroids.2019.108460

Abstract

In an endeavour to develop potent anti-tumor agents from diosgenin, a series of C-6 derived 1,2,3-triazolyl derivatives were designed and synthesized by employing Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction of novel azides - (22R,25R)-6β-azidospirostan-3β,5α-diol and 6β-azido-7α-hydroxyspirosta-1,4-dien-3-one with aryl(hetaryl)alkynes. All the derivatives were evaluated for cytotoxic activity by MTT assay against eight different human cancer cell lines: T-cellular leucosis (CEM-13), human monocytes (U-937), breast (MDA-MB-231, BT-474), prostate (DU-145) and glioblastoma (U-87MG, SNB-19, T98G). The results of this study suggested that 6-(4'-aryl-1',2',3'-triazolyl)spirostan-3,5-diols 2, 3, 4, 5 and 6 possessed a promising cytotoxic potential. The corresponding 6-substituted 7-hydroxy-1,4-spirostadien-3-ones shown less cytotoxity on the human cancer cells. Compounds 2, 3, 4, and 5 which demonstrated high grown inhibition against glioma cancer cells U-87 and T98G, and also on the human-derived N118669 primary glioblastoma cell line (with GI₅₀ values in the range of 5-9 μM), were not affected the growth of SNB-19 cells. The data revealed that phenyl, 4-methoxyphenyl, 4-fluorophenyl, 3,4,5-trimethoxyphenyl or 2-pyridinyl substituent in the triazole moiety at the C-6 position significantly improved the anti-tumor activity. The mentioned position at the spirostan core may be favourable for the synthesis of potent anticancer leads from diosgenin.

Keywords: Click chemistry; Cytotoxicity; Diosgenin; Spirostanes; Steroids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Chemistry Techniques, Synthetic
Humans
Spiro Compounds / chemistry*
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Antineoplastic Agents
Spiro Compounds
Triazoles