Facile preparation and preliminary cytotoxicity evaluation of dehydroepiandrosterone C-16 spiro-pyrrolidine derivatives
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ORIGINAL PAPER
Facile preparation and preliminary cytotoxicity evaluation of dehydroepiandrosterone C‑16 spiro‑pyrrolidine derivatives Hong‑Wen Tao1 · Wen‑Yu Peng1 · Jiang‑Chun Yuan1 · Qiang Li1 · Lu‑Yao Zeng1 · Xian‑Yong Yu1 · Ping‑Gui Yi1 Received: 7 January 2020 / Accepted: 9 September 2020 © Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract A facile synthesis of dehydroepiandrosterones derived by C-16 spiro-pyrrolidine and their cytotoxic evaluation are reported. Seven derivatives, 3a–3g, were prepared by the [3 + 2] cycloaddition reaction of the 16-arylidene dehydroepiandrosterone and the azomethine ylide, where the azomethine ylide was generated in situ from 11H-indeno[1,2-b]quinoxalin-11-one and sarcosine. Their cytotoxicity was evaluated on brine shrimp assay and the bioactivities represented by L C50 values were found in the range of 6.19–27.2 µg/mL. Among them, the activities of 3d and 3g are the best, as manifested by L C50 values less than 10 µg/mL. All products were confirmed by NMR, HR MS and X-ray analysis. Graphic abstract
Keywords [3 + 2] cycloaddition · Dehydroepiandrosterone · Steroidal spiro-pyrrolidine · Azomethine ylide
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11696-020-01346-4) contains supplementary material, which is available to authorized users. * Hong‑Wen Tao [email protected] 1
Key Laboratory of Theoretical Organic Chemistry and Functional Molecules, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, Hunan, People’s Republic of China
Chemical modification of natural steroids provides pharmaceutical chemists many products with amazing diversity in structure and bioactivity (Singh and Panda 2013). Among them, heterocyclic steroidal compounds belong to the prominent candidates for their potential anti-inflammatory, antioxidant, anti-cancer and anti-microbial activities (Gupta et al. 1996; Mohamed et al. 2012; Abdelhalim et al. 2007). The steroidal materials with spiro-pyrrolidine moiety represent an important family for the unique structure and significant anti-cancer activity (Fig. 1) (Babu and Raghunathan 2008; Yu et al. 2014, 2015; Gavaskar et al. 2016). For these novel spiro-heterocyclic compounds (Liu et al. 2013; Yang et al. 2015; Singh et al. 2016; Zhang et al. 2017; Zeng et al. 2018),
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Fig. 1 Reported steroidal spiro-pyrrolidine derivatives
the diverse structure will be expected to produce the diversity of biological activity. In our search for new structural and bioactive entities (Tao et al. 2018, 2019), a series of dehydroepiandrosterone spiro-pyr rolidine derivatives, 1″-N-methyl-spiro[2′,11″]-indeno[1,2-b]quinoxalinespiro[3′,16]-dehydroepiandrosterone-4′-arylpyrrolidines (Scheme 1), were obtained. Herein we report the synthesis, structure, and bioassay of these steroidal derivatives. They can be synthesized by the [3 + 2] cycloaddition reaction without catalyst, and
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