- Discovery of New Carbonyl Reductases Using Functional Metagenomics and Applications in Biocatalysis
-
Enzyme discovery for use in the manufacture of chemicals, requiring high stereoselectivities, continues to be an important avenue of research. Here, a sequence directed metagenomics approach is described to identify short chain carbonyl reductases. PCR from a metagenomic template generated 37 enzymes, with an average 25% sequence identity, twelve of which showed interesting activities in initial screens. Six of the most productive enzymes were then tested against a panel of 21 substrates, including bulkier substrates that have been noted as challenging in biocatalytic reductions. Two enzymes were selected for further studies with the Wieland Miescher ketone. Notably, enzyme SDR-17, when co-expressed with a co-factor recycling system produced the anti-(4aR,5S) isomer in excellent isolated yields of 89% and 99% e.e. These results demonstrate the viability of a sequence directed metagenomics approach for the identification of multiple homologous sequences with low similarity, that can yield highly stereoselective enzymes with applicability in industrial biocatalysis. (Figure presented.).
- Newgas, Sophie A.,Jeffries, Jack W. E.,Moody, Thomas S.,Ward, John M.,Hailes, Helen C.
-
p. 3044 - 3052
(2021/04/26)
-
- Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes
-
The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.
- Pola, Suresh,Shah, Shailesh R.,Pingali, Harikishore,Zaware, Pandurang,Thube, Baban,Makadia, Pankaj,Patel, Hoshang,Bandyopadhyay, Debdutta,Rath, Akshyaya,Giri, Suresh,Patel, Jitendra H.,Ranvir,Sundar,Patel, Harilal,Kumar, Jeevan,Jain, Mukul R.
-
-
- Synthesis method of N-ethoxycarbonyl-4-hydroxypiperidine
-
The invention discloses a synthesis method of N-ethoxycarbonyl-4-hydroxypiperidine and belongs to the technical field of organic chemistry. In the presence of a catalytic amount of ammonium chloride,4-hydroxypiperidine is added to hexamethyldisilazane for a reflux reaction, 4-trimethylsiloxypiperidine is obtained, an intermediate and diethyl carbonate are subjected to a sealed reaction at the high temperature, and N-ethoxycarbonyl-4-hydroxypiperidine is obtained. The method has the characteristics that raw materials are easy to obtain, the cost is low, factory operation is simple and convenient and the yield is high. In synthesis, highly toxic ethyl chloroformate is not used, and a method is provided for synthesis of the compound.
- -
-
Paragraph 0018; 0020; 0023; 0026
(2018/05/16)
-
- ANTI-BACTERIAL COMPOUNDS
-
A compound of Formula (II): for use in the prevention or treatment of a bacterial infection.
- -
-
Page/Page column 117; 118
(2017/06/28)
-
- Development of two diastereoselective routes towards trans-4-aminomethyl-piperidin-3-ol building blocks
-
Two diastereoselective, scaleable routes towards trans-3,4-disubstituted piperidines with a 4-hydroxymethyl-3-hydroxy or 4-aminomethyl-3-hydroxy substitution pattern are being described. In the first route, the 3,4-trans configuration was introduced regio- and diastereoselectively via a hydroboration/oxidation sequence starting from 4-hydroxymethylpyridine. In the second route, regioselective epoxide ring opening of N-benzyl-3,4-epoxy-piperidine was achieved with LiCN, in situ generated from acetocyanohydrin and LiNH2. The regioselectivity of both the hydroboration and the epoxide ring opening was positively influenced by the presence of the basic piperidine nitrogen. Both routes have been optimized to be performed at large scale.
- Gijsen, Harrie J.M.,De Cleyn, Michel J.A.,Love, Christopher J.,Surkyn, Michel,Van Brandt, Sven F.A.,Verdonck, Marc G.C.,Moens, Luc,Cuypers, Jef,Bosmans, Jean-Paul R.M.A.
-
p. 2456 - 2464
(2008/09/18)
-
- (Pyridylcyanomethyl)piperazines as orally active PAF antagonists
-
A series of (pyridylcyanomethyl)piperazines was prepared and evaluated for PAF-antagonist activity. Compounds were tested in vitro in a PAF-induced platelet aggregation assay and in vivo in a PAF-induced hypotension test in normotensive rats. Oral activity was ascertained through a PAF-induced mortality test in mice. The main structure-activity trends of the series were established. Activity was mainly found in four skeletons: 1-acyl-4-(3- pyridylcyanomethyl)-piperazine, 1-acyl-4-(4-pyridylcyanomethyl)piperazine, 1- acyl-4-(3-pyridylcyanomethyl)piperidine, and 1-acyl-4-cyano-4-(3- pyridylamino)piperidine. The acyl substituents, diphenylacetyl and 3,3- diphenylpropionyl, provided the most active compounds, and the introduction of an amine or hydroxy group in the 3,3-diphenylpropionyl substituent led to further improvement in oral activity. As a result, three of the most active compounds (100, 114, and 115) have been selected for further pharmacological development.
- Carceller,Almansa,Merlos,Giral,Bartroli,Garcia-Rafanell,Forn
-
p. 4118 - 4134
(2007/10/02)
-
- 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
-
4-[(Bicyclic heterocyclyl)methyl and -hetero]-piperidines having antihistaminic and serotonin-antagonistic properties which compounds are useful agents in the treatment of allergic diseases.
- -
-
-