title: Novel antiproliferative agents derived from lavendustin A.
abstract: The active partial structure of the potent tyrosine kinase inhibitor lavendustin A was derivatized in the search for novel agents against cellular proliferation. The antiproliferative potential of the new derivatives was determined using the human keratinocyte cell line HaCaT as the primary test system. Whereas the lavendustin A partial structure is ineffective in inhibiting cell proliferation, esterification of its carboxylic acid function leads to measurable antiproliferative activity. Additional O-methylation of the 2,5-dihydroxyphenyl moiety yields activity in the micromolar range. Further substantial increases in activity are achieved by replacing the nitrogen with oxygen and carbon within the 2,5-dimethoxyphenyl series (but not within the 2,5-dihydroxyphenyl analogs) leading to 5-[2-(2,5-dimethoxyphenyl) ethyl]-2-hydroxybenzoic acid methyl ester (13) as the most potent analog identified to date. These increases in antiproliferative activity are paralleled, however, by the disappearance of activity against the epidermal growth factor receptor-associated tyrosine kinase, suggesting another mechanism of action.
authors.affiliation: Department of Dermatology, SANDOZ Research Institute, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Nussbaumer
authors.forename: A P
authors.initials: AP
authors.lastname: Winiski
authors.forename: S
authors.initials: S
authors.lastname: Cammisuli
authors.forename: P
authors.initials: P
authors.lastname: Hiestand
authors.forename: G
authors.initials: G
authors.lastname: Weckbecker
authors.forename: A
authors.initials: A
authors.lastname: Stütz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010636:Phenols; C062898:lavendustin A; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases