Cellular analysis of disorazole C and structure-activity relationship of analogs of the natural product.
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.
Department of Chemistry, Center for Chemical Methodologies and Library Development, University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA. pwipf@pitt.edu
Peter
P
Wipf
Thomas H
TH
Graham
Andreas
A
Vogt
Rachel P
RP
Sikorski
Alexander P
AP
Ducruet
John S
JS
Lazo
D050256:Antimitotic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
D050256:Antimitotic Agents; D001688:Biological Products; D018942:Macrolides; D010080:Oxazoles; C436383:disorazole C1