Bifidenone: Structure–Activity Relationship and Advanced Preclinical Candidate

Bifidenone is a novel natural tubulin
polymerization inhibitor
that exhibits antiproliferative activity against a range of human
cancer cell lines, making it an attractive candidate for development.
A synthetic route was previously developed to alleviate supply constraints
arising from its isolation in microgram quantities from a Gabonese
tree. Using that previously published route, we present here 42 analogues
that were synthesized to examine the structure–activity relationship
of bifidenone derivatives. In addition to in vitro cytotoxicity data,
data from murine xenograft and pharmacokinetic studies were used to
evaluate the analogues. Compounds 45b and 46b were found to demonstrate promising efficacy in murine xenograft
experiments, and 46b had significantly more potent in
vitro antiproliferative activity against taxane-resistant cell lines
compared to that of paclitaxel.