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Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The aldolase-catalyzed reaction proceeds via two different mechanisms, a Schiff base formation (class I aldolases) or by Zn2+ activation (class II aldolases), as depicted in the opposite scheme for DHAP-dependent enzymes. The mechanism of class I aldolases (a) is characterized by the formation of an imine between the terminal amino group of a Lys residue and the carbonyl oxygen atom of the substrate DAHP. The imine may rearrange to an enamine that attacks nucleophilicly the aldehyde carbonyl carbon. Subsequent hydrolysis gives the new aldol and the free enzyme. The first steps in the reaction mechanism of the class II aldolases such as tagatose-1,6-diphosphate aldolase or fructose-1,6-diphosphate aldolase (b) are the binding of DAHP and the abstraction of a proton from the activated C1 by a functional group of the active site. The following steps (not shown), are glyceraldehyde-3-phosphate binding with subsequent C–C bond formation, and proton transfer.
On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andreas Sebastian Klein, Thomas Classen, Jörg Pietruszka
Statins decrease the cholesterol level and were blockbuster par excellence in affluent societies. Especially the chiral side-chain of atorvastatin (11) has been synthesized by many groups using biocatalysis with great success (Patel, 2009; Müller, 2004). The chemical company DSM was able to implement a multi-ton scale production based on the 2-deoxy-ribose-5-phosphate aldolase (DERA), which naturally cleaves the name giving substrate into acetaldehyde and glyceraldehyde-3-phosphate (Haridas et al., 2018). Since enzymes accelerate a given reaction but do not influence the thermodynamic equilibrium, the DERA can also be used in the aldol rather than the retro-aldol reaction (see Fig. 21.3). The precursor of the side-chain 9 can be produced in one reaction sequence, where DERA performs two consecutive aldol reactions: the first between acetaldehyde (7) and chloroacetaldehyde (8), and the second between previously formed aldol (8) and second molecule of acetaldehyde (7). The formed lactol 10 can be transformed into the respective pharmacophore of atorvastatin (11). This process takes advantage of DERA’s chemo- and stereoselectivity.
Cross-Linking of Collagen
Published in Marcel E. Nimni, Collagen, 1988
Mitsuo Yamauchi, Gerald L. Mechanic
At present, there are two routes in the Lysald pathway. One leads to the formation of reducible labile dehydro-histidinohydroxymerodesmosine (deH-HHMD) via aldol. Another leads to the formation of the nonreducible stable cross-link, histidinohydroxylysinonorleucine (HHL) (See below),28 via the iminium cross-link, dehydro-hydroxylysinonorleucine (deH-HLNL). The former probably involves two NH2-terminal nonhelical peptide regions in soft connective tissues,26,27 while the latter involves mainly one COOH-terminal nonhelical peptide region of the molecule in skin collagen28,60,63 and is most probably an end product crosslink in this route.61
Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Tiantian Fan, Yinchun Ji, Danqi Chen, Xia Peng, Jing Ai, Bing Xiong
As compound 14 showed the highest inhibition of TNF-α secretion and excellent kinase selectivity, the metabolic stability of compound 14 was evaluated in human liver microsomes. The suitable metabolic stability was observed on compound 14, T1/2 = 96.3 min, CL = 9.64 ml/min/kg, triggering for more in-depth research. However, we have done experiment on AO oxidative metabolism of compound 14 and P5. Both compound 14 and P5 could undergo mono oxidative metabolism in the human liver cytosol incubation system. The addition of aldol oxidase inhibitor raloxifene and menadione significantly inhibited the production of oxidative metabolites. The result showed both compound 14 and P5 were metabolic substrates of AO oxidase.
(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Le Cong Huan, Cao Viet Phuong, Le Cong Truc, Vo Nguyen Thanh, Hai Pham-The, Le-Thi-Thu Huong, Nguyen Thi Thuan, Eun Jae Park, A Young Ji, Jong Soon Kang, Sang-Bae Han, Phuong-Thao Tran, Nguyen-Hai Nam
The target acetohydrazides incorporating quinazolin-4(3H)-one (5a–z, 6a–g, 7a–b) were synthesised via four step pathway, as illustrated in scheme 1. The first step was a Niementowski condensation of anthranilic acid (1a) or 5-substituted-2-aminobenzoic acid (1b–d) and formamide at 120 °C to obtain quinazoline-4(3H)-one derivatives (2a–d) in quantitative yield (93–97%). In the second step, an acylation between quinazoline-4(3H)-one derivatives (2a–d) and ethyl chloroacetate under basic conditions (K2CO3) in acetone with a catalytic amount of KI gave the selectively N3-alkylated intermediate esters 3a–d29. These esters 3a–d participated in futher acyl nucleophile substitution with hydrazine monohydrate at the third step. This reaction proceeded smoothly in ethanol under refluxing condition. The final step in the pathway involved an aldol condensation of hydrazids 4a–d with benzaldehydes or isatins. The desired products 5a–z, 6a–g, 7a–b were obtained in moderate overall yields.
Acetylenes: cytochrome P450 oxidation and mechanism-based enzyme inactivation
Published in Drug Metabolism Reviews, 2019
The mechanism for de-ethynylation is unclear, but a mechanism based on a reverse aldol reaction subsequent to trapping of the ketene metabolite by a thiol agent, shown in Figure 10 as RSH, provides a possible explanation. The intervention of cysteine and glutathione in the oxidative metabolism of acetylenes, resulting inter alia in cleavage of the triple bond to leave behind an aldehyde group, has been reported (Subramanian et al. 2011), but these reactions do not seem to relate to the process of de-ethynylation described here.