discodermolide and Triple-Negative-Breast-Neoplasms

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC

Topics: A549 Cells; Alkanes; Area Under Curve; Carbamates; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Lactones; Molecular Structure; Ovarian Neoplasms; Pyrones; Taxoids; Triple Negative Breast Neoplasms; Tubulin Modulators