Synthesis and biological evaluation of platensic alcohol as an adamantane surrogate in antitumor drug lead adaphostin. (15th September 2021)

• Record Type: Journal Article
• Authors: Wen, Zhongqing; Duan, Yanwen; Xiong, Yi; Huang, Yong
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 48(2021)
• Publication Date: 2021-09-15
• Subjects: VQUSQZUFZKLKJS-XIYBEUOYSA-N -- YJZSUCFGHXQWDM-ONHXBKDTSA-N; Platensimycin -- Adamantane -- Adaphostin -- Reactive oxygen species -- Histone deacetylase inhibitors -- Vorinostat; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128270
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A lipophilic natural product fragment was used as the adamantane surrogate. Preparation of compound 4b with comparable cytotoxicity and serum stability with adaphostin. The stronger synergistic effects of 4b with HDACi vorinostat. Abstract: Adamantane has been widely used as a "lipophilic bullet" in drug discovery and development, due to its unique diamond-like architecture with benign pharmacological/ pharmaceutical properties. Platensimycin is a natural product isolated from a soil streptomycete, which contains an adamantane-like moiety extensively modified from a diterpenoid precursor. In the current study, platensic alcohol was semisynthesized from platensimycin and used as an adamantane surrogate in anticancer drug lead adaphostin. The resulting hybrid platensic alcohol/adaphostin compounds, eg. 4a and 4b, exhibited similar cytotoxic activity with adaphostin against the tested cancer cell lines. In particular, 4b generates significantly more reactive oxygen species (ROS) and shows stronger synergy with the clinically used histone deacetylase inhibitor vorinostat than adaphostin, probably due to the presence of two hydroquinone groups. Density functional theory calculation supports that there could be certain π-π stacking interaction in 4b in aqueous solution, which might explain that 4b has similar serum stability with adaphostin. Our study not only leads to the identification of 4b as a potent ROS generating agent, but showcases a simple scaffold hopping strategy to harvest lipophilic scaffolds from natural products.