Total synthesis and biological evaluation of novel C2–C6 region analogues of dictyostatin

• Published in: Bioorganic & medicinal chemistry Vol. 17; no. 6; pp. 2282 - 2289
• Main Authors: Paterson, Ian, Gardner, Nicola M., Guzmán, Esther, Wright, Amy E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.03.2009
• Subjects: Antitumour; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Macrolide; Macrolides - chemical synthesis; Macrolides - chemistry; Macrolides - pharmacology; Models, Molecular; Spectrum Analysis - methods; Total synthesis; Tubulin; Antitumour; Tubulin; Macrolide; Total synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.10.084

Novel analogues of the microtubule-stabilising agent dictyostatin were designed, synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines. By exploiting a Still–Gennari HWE coupling with a common C11–C26 aldehyde, a series of C2–C6 modified analogues of the microtubule-stabilising marine natural product dictyostatin were synthesised and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the (P-glycoprotein efflux-mediated) Taxol-resistant NCI/ADR cell line. Removal of the C6 methyl substituent in dictyostatin was found to be well tolerated and led to the retention of antiproliferative activity in the low nanomolar range (IC 50 = 43 nM in the NCI/ADR cell line), while partial and full saturation of the (2 Z, 4 E)-dienoate region led to a progressive reduction in biological potency. The lactone ring size was found to be critical, as C21 to C19 translactonisation to afford 20-membered isodictyostatin analogues led to a significant loss of cytotoxicity. In a series of incubatory experiments performed on the PANC-1 cell line, all three of the 22-membered macrolide analogues acted in an analogous fashion to dictyostatin, through a mechanism of microtubule stabilization, causing both an accumulation of cells at the G2/M phase and formation of characteristic dense intracellular microtubule bundles.