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Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin
Author(s) -
Huang David S.,
Wong Henry L.,
Georg Gunda I.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700084
Subject(s) - lactone , chemistry , stereochemistry , steric effects , substituent , natural product , adduct , conjugate , isopropyl , cytotoxicity , organic chemistry , biochemistry , in vitro , mathematical analysis , mathematics
Abstract Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α‐tubulin via conjugate addition into the natural product's α,β‐unsaturated lactone. Although pironetin's α,β‐unsaturated lactone is involved in its binding to tubulin, the structure–activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure–activity relationships at the C4 and C5 positions of the α,β‐unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β‐unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not.