78507-19-4Relevant academic research and scientific papers
Phenyl ether- and aniline-containing 2-aminoquinolines as potent and selective inhibitors of neuronal nitric oxide synthase
Cinelli, Maris A.,Li, Huiying,Pensa, Anthony V.,Kang, Soosung,Roman, Linda J.,Martásek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
supporting information, p. 8694 - 8712 (2015/11/25)
Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
N-Nitrosobenzylmethylamine hydroxylation and coumarin 7-hydroxylation: Catalysis by rat esophageal microsomes and cytochrome P450 2A3 and 2A6 enzymes
Von Weymarn, Linda B.,Felicia, Nadia D.,Ding, Xinxin,Murphy, Sharon E.
, p. 1254 - 1261 (2007/10/03)
N-Nitrosobenzylmethylamine (NBzMA) is a potent and selective esophageal carcinogen in the rat and may be a causative agent for human esophageal cancer. This nitrosamine, like most, must be metabolically activated to exert its carcinogenic potential. NBzMA may be metabolized by P450-catalyzed methyl or methylene hydroxylation; the latter is believed to be the activation pathway. The sensitivity of the esophagus to NBzMA-induced tumorigenesis is believed to be due, at least in part, to the presence of efficient P450 catalysts in this tissue. However, while it was reported almost 20 years ago that the rat esophagus catalyzes the methylene hydroxylation of NBzMA, the P450 that catalyzes this reaction has yet to be identified. We report here that human P450 2A6 and the closely related extrahepatic rat enzyme P450 2A3 both efficiently catalyze NBzMA methylene hydroxylation, characterized as benzaldehyde formation. The catalytic efficiency of P450 2A3 in this reaction was 3-fold greater than that of P450 2A6, 7.6 (K(m) = 0.63 ± 0.18 μM and the V(max) = 4.8 nmol min-1 nmol of P450-1) versus 2.3 (K(m) = 6.7 ± 2.9 μM and the V(max) = 15.7 nmol min-1 nmol of P450-1), respectively. Both enzymes catalyzed methylene hydroxylation at least 4-fold more efficiently than methyl hydroxylation. In addition, P450 2A6, but not P450 2A3, catalyzed benzyl ring hydroxylation, generating N-(p-hydroxybenzyl)methylamine. The identity of this metabolite was confirmed by synthesis of a standard and LC/MS and LC/MS/MS analysis. P450 2A6 is an efficient coumarin 7-hydroxylase, and we report here that P450 2A3 is an equally good catalyst of this reaction (K(m) = 1.7 ± 0.41 μM and V(max) = 1.7 ± 0.08 nmol min-1 nmol of P450- 1). Rat esophageal microsomes (REM), like P450 2A3, were efficient catalysts of NBzMA methylene hydroxylation. However, in contrast to P450 2A3, the major product of this reaction was the product of benzaldehyde oxidation, benzoic acid. Antibody to the closely related mouse P450, 2A5, did not inhibit REM- catalyzed NBzMA metabolism, and most importantly, REM did not catalyze the 7- hydroxylation of coumarin. Therefore, P450 2A3 does not appear to be the P450 in the rat esophagus responsible for catalyzing the methylene hydroxylation of NBzMA.
REACTIONS RETRODIENIQUES-XI SYNTHESE DE COMPOSES POLYINSATURES REACTIFS PAR DOUBLE REACTION DE RETRO-DIELS-ALDER
Lasne, M. C.,Ripoll, J. L.,Denis, J. M.
, p. 503 - 508 (2007/10/02)
Double retro-Diels-Alder cleavage by flash thermolysis gave the new, unstable polyunsaturated ketones and hydrocarbons 1-5 for which NMR, IR and UV spectra at low temperature are reported.The Diels-Alder adducts of compounds 1-3 with various dienes, the 1,6-additions of several nucleophilic agents with 4, and the isomerisation of 5 in p-ethynylstyrene support the proposed structures.
