2. Academic Validation
  3. Synthesis and biological evaluation of platensic alcohol as an adamantane surrogate in antitumor drug lead adaphostin

Synthesis and biological evaluation of platensic alcohol as an adamantane surrogate in antitumor drug lead adaphostin

  • Bioorg Med Chem Lett. 2021 Sep 15:48:128270. doi: 10.1016/j.bmcl.2021.128270.
Zhongqing Wen 1,  Yanwen Duan 2,  Yi Xiong 1,  Yong Huang 3
Affiliations

Affiliations

  • 1 Xiangya International Academy of Translational Medicine at Central South University, Changsha, Hunan 410013, China.
  • 2 Xiangya International Academy of Translational Medicine at Central South University, Changsha, Hunan 410013, China; Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery, China; National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, Hunan 410011, China.
  • 3 Xiangya International Academy of Translational Medicine at Central South University, Changsha, Hunan 410013, China; National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery, Changsha, Hunan 410011, China. Electronic address: jonghuang@csu.edu.cn.
PMID: 34284106 DOI: 10.1016/j.bmcl.2021.128270
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.

Keywords

Adamantane; Adaphostin; Histone deacetylase inhibitors; Platensimycin; Reactive oxygen species; Vorinostat.

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