title: Exploring a cascade Heck-Suzuki reaction based route to kinase inhibitors using design of experiments.
abstract: Design of Experiments (DoE) has been used to optimize a diversity oriented palladium catalyzed cascade Heck-Suzuki reaction for the construction of 3-alkenyl substituted cyclopenta[b]indole compounds. The obtained DoE model revealed a reaction highly dependent on the ligand. Guided by the model, an optimal ligand was chosen that selectively delivered the desired products in high yields. The conditions were applicable with a variety of boronic acids and were used to synthesize a library of 3-alkenyl derivatized compounds. Focusing on inhibition of kinases relevant for combating melanoma, the library was used in an initial structure-activity survey. In line with the observed kinase inhibition, cellular studies revealed one of the more promising derivatives to inhibit cell proliferation via an apoptotic mechanism.
authors: Department of Chemical and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, Sweden. jerker@chalmers.se.
authors: Andreas
authors: A
authors: Ekebergh
authors: Christine
authors: C
authors: Lingblom
authors: Peter
authors: P
authors: Sandin
authors: Christine
authors: C
authors: Wennerås
authors: Jerker
authors: J
authors: Mårtensson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D010636:Phenols; D047428:Protein Kinase Inhibitors; C083368:scytonemin; D010165:Palladium; D010770:Phosphotransferases