Cellular analysis of disorazole C-1 and structure-activity relationship of analogs of the natural product

• Published in: Chemical biology & drug design Vol. 67; no. 1; pp. 66 - 73
• Main Authors: Wipf, P, Graham, TH, Vogt, A, Sikorski, RP, Ducruet, AP, Lazo, JS
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.01.2006
• Subjects: Biochemistry & Molecular Biology; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; natural products; cell cycle; SAR; gliding bacteria; disorazoles; tubulin; BIOLOGICAL EVALUATION; conformational analysis; mitosis; INHIBITOR; macrolide
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2005.00313.x

Structure-activity analyses of synthetic disorazole C-1 and eight of its analogs indicate that the presence of a vinyl oxirane moiety or a tetraene sequence is not necessary for potent cytotoxic and antimitotic properties. Using an automated multiparameter fluorescence-based cellular assay to simultaneously probe the effects of disorazole analogs on cellular microtubules, mitotic arrest, and cytotoxicity, we found that disorazole C-1 enhanced the mitotic index and chromatin condensation and arrested cells in the G2/M phase of the cell cycle. All structural analogs and synthesis precursors of disorazole C-1 were at least two orders of magnitude less potent than the parent compound, thus indicating that both the functional group array and the three-dimensional conformation of the parent compound are critical for interaction with the biological target. We conclude that disorazole C-1 is a potent inducer of mitotic arrest and hypothesize that this biological activity may be mediated by microtubule perturbation.