title: Structure-activity relationship studies on a novel class of antiproliferative agents derived from Lavendustin A. Part I: Ring A modifications.
abstract: The potent antiproliferative agent SDZ LAP 977, which has shown efficacy in a clinical proof of concept study in actinic keratosis patients, has been previously demonstrated to block the cell cycle in mitosis. In the present study, we further explored the mode of action: SDZ LAP 977 binds to the "colchicine binding site" on tubulin and, thus, inhibits tubulin polymerization in vitro. Moreover, we established structure-activity relationships for the effect of modifications in the 2,5-dimethoxyphenyl moiety ("ring A") of the molecule on in vitro antiproliferative activity.
authors.affiliation: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1230 Vienna, Austria. nussbaumer@lead-discovery.de
authors.forename: Peter
authors.initials: P
authors.lastname: Nussbaumer
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Winiski
mesh_terms: D001665:Binding Sites; D048708:Cell Growth Processes / Q000187:drug effects; D002460:Cell Line; D003078:Colchicine / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
chemical_list: D010636:Phenols; D047428:Protein Kinase Inhibitors; D014404:Tubulin; C062898:lavendustin A; D003078:Colchicine