Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3201195 for study in Werner syndrome cells.
5-Aminopyrazol-4-yl ketones are prepared rapidly and efficiently using microwave dielectric heating from beta-ketonitriles by treatment with N,N'-diphenylformamidine followed by heterocyclocondensation by irradiation with a hydrazine. The inhibitory activity of RO3201195 prepared by this methodology was confirmed in hTERT-immortalized HCA2 and WS dermal fibroblasts at 200nM concentration, both by ELISA and immunoblot assay, and displays excellent kinase selectivity for p38alpha MAPK over the related stress-activated kinase JNK.
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK. Bagleymc@cardiff.ac.uk
Mark C
MC
Bagley
Terence
T
Davis
Matthew C
MC
Dix
Paola G S
PG
Murziani
Michal J
MJ
Rokicki
David
D
Kipling
D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008872:Microwaves; D008956:Models, Chemical; D009281:Naphthalenes / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry; D020033:Protein Isoforms; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010671:Phenylurea Compounds
D004791:Enzyme Inhibitors; D007659:Ketones; D048670:MAP Kinase Kinase 4; D009281:Naphthalenes; D009570:Nitriles; D020033:Protein Isoforms; D011720:Pyrazoles; D048051:p38 Mitogen-Activated Protein Kinases; C509704:5-amino-1-(4-fluorophenyl)-4-(3-(2,3-dihydroxypropoxy)benzoyl)pyrazole; C452139:doramapimod; D010671:Phenylurea Compounds