Rational Design, Synthesis, and Mechanism of (3S,4R)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic Acid: Employing a Second-Deprotonation Strategy for Selectivity of Human Ornithine Aminotransferase over GABA Aminotransferase was written by Zhu, Wei;Butrin, Arseniy;Melani, Rafael D.;Doubleday, Peter F.;Ferreira, Glaucio Monteiro;Tavares, Mauricio T.;Habeeb Mohammad, Thahani S.;Beaupre, Brett A.;Kelleher, Neil L.;Moran, Graham R.;Liu, Dali;Silverman, Richard B.. And the article was included in Journal of the American Chemical Society in 2022.Electric Literature of C8H10NO6P The following contents are mentioned in the article:
Human ornithine aminotransferase (hOAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacol. inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators (CPP-115 and OV329). Inspired by the inactivation mechanistic difference between these two aminotransferases, a series of analogs were designed and synthesized, leading to the discovery of analog 10b (I) as a highly selective and potent hOAT inhibitor. Intact protein mass spectrometry, protein crystallog., and dialysis experiments indicated that 10b was converted to an irreversible tight-binding adduct (34)(II) in the active site of hOAT, as was the unsaturated analog (11)(III). The comparison of kinetic studies between 10b and 11 suggested that the active intermediate (17b)(IV) was only generated in hOAT and not in GABA-AT. Mol. docking studies and pKa computational calculations highlighted the importance of chirality and the endocyclic double bond for inhibitory activity. The turnover mechanism of 10b was supported by mass spectrometric anal. of dissociable products and fluoride ion release experiments Notably, the stopped-flow experiments were highly consistent with the proposed mechanism, suggesting a relatively slow hydrolysis rate for hOAT. The novel second-deprotonation mechanism of 10b contributes to its high potency and significantly enhanced selectivity for hOAT inhibition. This study involved multiple reactions and reactants, such as (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7Electric Literature of C8H10NO6P).
(4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7) belongs to pyridine derivatives. The ring atoms in the pyridine molecule are sp2-hybridized. The nitrogen is involved in the π-bonding aromatic system using its unhybridized p orbital. The lone pair is in an sp2 orbital, projecting outward from the ring in the same plane as the σ bonds. Many analogues of pyridine are known where N is replaced by other heteroatoms . Substitution of one C–H in pyridine with a second N gives rise to the diazine heterocycles (C4H4N2), with the names pyridazine, pyrimidine, and pyrazine.Electric Literature of C8H10NO6P