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Synthesis and biological evaluation of platensic alcohol as an adamantane surrogate in antitumor drug lead adaphostin.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Sep 15; Vol. 48, pp. 128270. Date of Electronic Publication: 2021 Jul 17. - Publication Year :
- 2021
-
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.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adamantane chemical synthesis
Adamantane chemistry
Adamantane pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Line
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors chemistry
Histone Deacetylases metabolism
Humans
Hydroquinones chemical synthesis
Hydroquinones chemistry
Molecular Structure
Reactive Oxygen Species metabolism
Structure-Activity Relationship
Adamantane analogs & derivatives
Alcohols chemistry
Antineoplastic Agents pharmacology
Histone Deacetylase Inhibitors pharmacology
Hydroquinones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 48
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34284106
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.128270