Cellular analysis of disorazole C1 and structure-activity relationship of analogs of the natural product

Abstract

Structure-activity analyses of synthetic disorazole C1 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 C1 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 C1 is a potent inducer of mitotic arrest and hypothesize that this biological activity may be mediated by microtubule perturbation. © 2005 Blackwell Munksgaard.