134198-11-1Relevant articles and documents
SERINE/THREONINE PAK1 INHIBITORS
-
, (2013/03/26)
Compounds having the formula I wherein A, Z, R1a, R1b, R2, R3, R4, R5, R6, R7, R9, R10, Ra, Rb and n are as defined herein are inhibitors of PAK1. Also disclosed are compositions and methods for treating cancer and hyperproliferative disorders.
Hypersensitive mechanistic probe studies of cytochrome P450-catalyzed hydroxylation reactions. Implications for the cationic pathway
Toy, Patrick H.,Newcomb, Martin,Hollenberg, Paul F.
, p. 7719 - 7729 (2007/10/03)
Details of the mechanism of cytochrome P450-catalyzed hydroxylation reactions were investigated by oxidation of trans-2-phenyl-1- alkylcyclopropanes (alkyl = methyl (1), ethyl (2), 1-propyl (3), 1- methylethyl (4)) and trans-2-(4-(trifluoromethyl)phenyl)-1-alkylcyclopropanes (alkyl = methyl (5), ethyl (6)). The syntheses of 3 and 6 and their possible oxidation products are reported. Oxidation of the probes with the cytochrome P450 isozyme CYP2B1 gave unrearranged cyclopropylcarbinols as major products and small amounts of ring-opened alcohol products in all cases except for 4. Phenolic products also were produced from substrates 1-4. The maximum lifetimes of putative radical intermediates were less than 1 ps, and the results with substrate 4 require that no intermediate was formed. The results were analyzed in the context of recent mechanistic proposals for cytochrome P450-catalyzed hydroxylations. Oxidation of a 'radical' component in the transition state of an insertion reaction to produce a cation is inconsistent with the results. The results also provide little support for a new alternative mechanism for hydroxylation, the agostic complex model (Collman, J.P.; Chien, A. S.; Eberspacher, T. A.; Brauman, J. I. J. Am. Chem. Soc. 1998, 120, 425). Formation of 'cationic' rearrangement products via solvolysis of first-formed protonated alcohol products produced by insertion of the 'OH+' moiety from iron-complexed hydrogen peroxide also is not supported by the results. The most consistent mechanistic description is the recently reported multistate reactivity paradigm (Shaik, S.; Filatov, M.; Schroder, D.; Schwarz, H. Chem. Eur. J. 1998, 4, 193).