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Proteases as Catalysts in Protecting Group Chemistry
Published in Willi Kullmann, Enzymatic Peptide Synthesis, 1987
In earlier studies on protease-catalyzed peptide bond formation, the α-COOH-protection of amine components had been accomplished by the anilide group.30,11 Anilides were readily obtained by incubating the respective Nα-protected amino acid with aniline in the presence of papain.3” In a comparative investigation, Fox et al.32 show that the efficiency of the papain-mediated introduction of the anilide group was in the following order (pH, ca. 5.0): Nα-benzoylated leucine, -alanine, -glycine, and -valine. In another report, Carty and Kirschenbaum showed33 that chymopapain was 20% more active than papain in promoting the formation of Bz-Gly-NHPh from Bz-Gly-OH and aniline. The anilide protection of α-carboxyl functions may actually have favored the synthesis of model peptides by reducing their solubility. However, in general this kind of protection is completely inadequate because it lacks one essential requirement of a suitable temporary or permanent protecting group, namely the selective reversibility of reaction. Indeed anilides cannot be chemically removed without seriously impairing the integrity of the newly formed peptide chain.
Phosphorus containing analogues of SAHA as inhibitors of HDACs
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Michael D. Pun, Hsin-Hua Wu, Feyisola P. Olatunji, Britany N. Kesic, John W. Peters, Clifford E. Berkman
In recent work, much attention has been towards increasing the potency of HDACi molecules and improving selectivity for certain isoenzymes. Negmeldin et al. modified the C2 position of SAHA with a n-hexyl to exploit a wider active site entrance of HDAC6/8. This compound resulted in a 49- to 300-fold HDAC6/8 (IC50 = 0.6 and 2.0 µM) selectivity over HDAC1-320. Procainamide-SAHA fused inhibitors proposed by Nardella et al. targeted post translational modifications in the malaria parasite plasmodium falciparum. This compound combines SAHA, a potent pan-HDAC inhibitor with a DNA methyltransferase inhibitor procainamide. The lead SAHA/procainamide fusion molecule was fully active in drug resistant plasmodium falciparum isolates (IC50 = 41 nM) and human HDAC6 (IC50 = 14 nM)21. Another strategy for optimisation of SAHA derivatives is replacing the anilide with different hydrophobic functional groups. Huang et al. synthesised and evaluated SAHA derivatives with osthole fused to the aliphatic hydroxamate core. Their best compound showed potency and selectivity similar to SAHA with moderate selectivity towards HDAC6 (IC50 = 14 nM)22.
Transition state analogue imprinted polymers as artificial amidases for amino acid p-nitroanilides: morphological effects of polymer network on catalytic efficiency
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Divya Mathew, Benny Thomas, K. S. Devaky
The porogenic solvents have a prominent role in fabricating the well-defined 3D cavity in the polymer matrix. The catalytic properties of the polymer catalysts like substrate stereo-specificity, substrate shape-selectivity, substrate specificity and Michaelis–Menten behaviour are found to be dependent on the solvent composition of the amidolytic reaction medium. The polymer prepared in DMSO is catalytically more efficient and obeys Michaelis–Menten kinetics in 1:9 ACN–Tris HCl buffer, while that prepared in CHCl3 is hydrolytically active in 9:1 ACN–Tris HCl buffer solution. The polymer catalyst exhibits solvent memory in the amidolytic reactions as in the case of template rebinding. Binding to the anilide is evaluated from the Michaelis–Menten constant Km and binding to the TSA can be estimated from the competitive inhibition caused by the added TSA during the catalytic amidolysis.
Strained contacts with the cell membrane may influence ligand affinity to G protein coupled receptors: a case of free fatty acid receptor 1 agonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Alexey Lukin, Anna Bakholdina, Mikhail Chudinov, Oleksandra Onopchenko, Elena Zhuravel, Sergey Zozulya, Maxim Gureev, Mikhail Krasavin
Earlier, we reported on the discovery of novel FFA1 agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold7. Out of this series, 4-(3-methyl)phenyl anilide 1 emerged as a potent (FFA1 EC50 0.76 µM) lead with high stability in plasma and in the presence of liver microsomes. Encouraged by this result, we proceeded to explore other substituted biphenyls in the carboxamide portion of the lead series and synthesised a number of new derivatives 2 belonging to this class (Figure 1).