75343-75-8Relevant academic research and scientific papers
Conformational Dynamics-Guided Loop Engineering of an Alcohol Dehydrogenase: Capture, Turnover and Enantioselective Transformation of Difficult-to-Reduce Ketones
Liu, Beibei,Qu, Ge,Li, Jun-Kuan,Fan, Wenchao,Ma, Jun-An,Xu, Yan,Nie, Yao,Sun, Zhoutong
supporting information, p. 3182 - 3190 (2019/05/15)
Directed evolution of enzymes for the asymmetric reduction of prochiral ketones to produce enantio-pure secondary alcohols is particularly attractive in organic synthesis. Loops located at the active pocket of enzymes often participate in conformational changes required to fine-tune residues for substrate binding and catalysis. It is therefore of great interest to control the substrate specificity and stereochemistry of enzymatic reactions by manipulating the conformational dynamics. Herein, a secondary alcohol dehydrogenase was chosen to enantioselectively catalyze the transformation of difficult-to-reduce bulky ketones, which are not accepted by the wildtype enzyme. Guided by previous work and particularly by structural analysis and molecular dynamics (MD) simulations, two key residues alanine 85 (A85) and isoleucine 86 (I86) situated at the binding pocket were thought to increase the fluctuation of a loop region, thereby yielding a larger volume of the binding pocket to accommodate bulky substrates. Subsequently, site-directed saturation mutagenesis was performed at the two sites. The best mutant, where residue alanine 85 was mutated to glycine and isoleucine 86 to leucine (A85G/I86L), can efficiently reduce bulky ketones to the corresponding pharmaceutically interesting alcohols with high enantioselectivities (～99% ee). Taken together, this study demonstrates that introducing appropriate mutations at key residues can induce a higher flexibility of the active site loop, resulting in the improvement of substrate specificity and enantioselectivity. (Figure presented.).
Ligand-Free Iridium-Catalyzed Dehydrogenative ortho C?H Borylation of Benzyl-2-Pyridines at Room Temperature
Yang, Yuhuan,Gao, Qian,Xu, Senmiao
supporting information, p. 858 - 862 (2019/01/04)
A convenient and ligand-free iridium-catalyzed dehydrogenative ortho C?H borylation of benzyl-2-pyridines has been developed. The reaction proceeds smoothly at room temperature using pinacolborane as a borylating reagent in the presence of catalytic amount of [IrOMe(COD)]2. The reaction is compatible with many functional groups, providing a vast array of ortho borylated products in moderate to excellent yields with excellent selectivities. (Figure presented.).
Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter
Froimowitz, Mark,Gu, Yonghong,Dakin, Les A.,Nagafuji, Pamela M.,Kelley, Charles J.,Parrish, Damon,Deschamps, Jeffrey R.,Janowsky, Aaron
, p. 219 - 232 (2007/10/03)
Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.
