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Biocatalytic Reduction of Organic Compounds by Marine-Derived Fungi
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Gabriel S. Baia, David E. Q. Jimenez, André Luiz Meleiro Porto
Enoate reductases (EnoRs) can catalyze the NADH-dependent reduction of C=C bonds of nonactive enolates such as cyclic ketones, methyl ketones and α,β-unsaturated aldehydes. Dobrijevic et al. [8] described the use of the EnoRs pQR1907, pQR1908, pQR1909, pQR1440, pQR1442, pQR1443 in the reduction of 2-methylcyclohex-2-en-1-one to 2-methylcyclohexan-1-one. The reduction reaction conditions were 30°C, 600 rpm in Tris-HCl for 24 h. The EnoRs produced the reduced product (R)-2-methylcyclohexan-1-one in 39–99% yields and 83–99% ee of the R-enantiomer observed in Figure 15.2 [8].
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The two phenolic aromatic ring systems of curcumin are joined by a heptene chain containing two α,β-unsaturated carbonyl groups capable of forming stable enols which can be readily deprotonated to enolates. Thus, the molecule can exist in several tautomeric forms, including a 1,3-diketo form and two equivalent enol forms (Figure 12.31). The enol form is more energetically stable in organic solvents and in the solid phase, while the 1,3-diketo form dominates in aqueous solvents including water itself. It is noteworthy that the α,β-unsaturated carbonyl groups are good Michael acceptors and can undergo nucleophilic addition, which may contribute to the molecule’s mechanism of action.
Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The α hydrogens of a ketone can readily be deprotonated with a base: α substitution reactions involve replacement of the αH with another group via an enolate. Useful reactions in synthesis include aldol condensations, where two ketones are combined in an alkylation reaction. In each case, a new C2–C3 bond is formed. This is a common strategy in organic synthesis because of the versatility of the C2–C3 bond in making new compounds. Ketones can also be used as a starting material for making alkenes, which provides an opportunity for a whole new set of organic reactions and alternative synthetic routes towards producing a target molecule.
Discovery of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives as a novel selective inhibitor scaffold of JNK3
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Youri Oh, Miyoung Jang, Hyunwook Cho, Songyi Yang, Daseul Im, Hyungwoo Moon, Jung-Mi Hah
The synthetic process of 3-alkyl-5-aryl-1-pyrimidyl-1H-pyrazole derivatives is shown in Scheme 1. We started with methyl ketones containing various aryl groups substituted (1) and formed enolate with sodium methoxide to react with dimethyl oxalate to produce beta ketone (2)15. The Knorr pyrazole synthesis was employed to form the pyrazole cores (3) using hydrazinyl pyrimidine and beta ketone16. After that, pyrazoyl ester was converted to alcohol (4) using lithium aluminium hydride17. The nitrile was introduced by the SN2 reaction with sodium cyanide following mesylation (5). Through the oxidation with potassium peroxymonosulfate of methyl sulphide to methylsulfone, a variety of amino groups were introduced to the pyrimidyl moiety (SNAr)18,19; then the terminal amino group was deprotected and acylated to give the final products (7a–d, 10a–f). For compounds 7e–f, 8a–f, and 9a–f, cyclopropylcarboxylated amine were directly incorporated. The terminal nitrile group was changed to an ester (11a) and carboxamide (12a) through Scheme 2. They were synthesised through hydrolysis of the 10a performed at different conditions.
Design, synthesis, and biological evaluation of novel androst-17β-amide structurally related compounds as dual 5α-reductase inhibitors and androgen receptor antagonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Kejing Lao, Guoliang Xun, Xingchun Gou, Hua Xiang
As the 5α-reductase isozymes have not been purified and crystallized due to their unstable nature, the design and optimisation of novel 5α-reductase inhibitor mainly relies on structure-based optimisation approach. 5α-reductase inhibitors are possible to postulate two different transition states (TS): the “substrate like” TS (S-TS) and the “product like” TS (P-TS) (Figure 2)19. For S-TS inhibitors, stabilisation of the proposed enolate intermediate is thus an obvious strategy for the design of potential inhibitors, and a number of compounds that satisfy this requirement have been produced. Thus it can be seen that introducing electron-withdrawing group in A ring and B ring is beneficial for inhibitory activity.
Linkers in fragment-based drug design: an overview of the literature
Published in Expert Opinion on Drug Discovery, 2023
Dylan Grenier, Solène Audebert, Jordane Preto, Jean-François Guichou, Isabelle Krimm
A four-carbon chain was proposed for HSP90 inhibitors by Barker et al. [17]. Interestingly, the authors observed that the second fragment exhibited different binding modes depending on the presence or absence of the first fragment. Fragment linking required two main steps, the formation of a carbon-carbon bond by the reaction of an enolate with a halide and an aromatic nucleophilic substitution on a chloro-purine cycle.