Novel Steroidal 5α,8α-Endoperoxide Derivatives with Semicarbazone/Thiosemicarbazone Side-chain as Apoptotic Inducers through an Intrinsic Apoptosis Pathway: Design, Synthesis and Biological Studies

A series of novel steroidal 5&#945;,8&#945;-endoperoxide derivatives bearing semicarbazone (<b>7a</b>&#8722;<b>g</b>) or thiosemicarbazone (<b>7h</b>&#8722;<b>k</b>) side chain were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, HCT-116, MCF-7, and A549) using the MTT assay <i>in vitro</i>. The results showed that compound <b>7j</b> exhibited significant cytotoxic activity against HepG2 cells (IC₅₀ = 3.52 &#956;M), being more potent than ergosterol peroxide. Further cellular mechanism studies in HepG2 cells indicated that compound <b>7j</b> triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential (MMP), which was associated with up-regulation of Bax, down-regulation of Bcl-2, activation levels of the caspase cascade, and formation of reactive oxygen species (ROS). The above findings indicated that compound <b>7j</b> may be used as a promising skeleton for antitumor agents with improved efficacy.

Abstract licence: CC BY

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