1. Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)
T N Johansen, K Frydenvang, B Ebert, U Madsen, P Krogsgaard-Larsen Chirality. 1997;9(5-6):529-36. doi: 10.1002/(SICI)1520-636X(1997)9:5/63.0.CO;2-P.
We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).
2. Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks
Wei Wei, Rama Kanwar Khangarot, Lothar Stahl, Cristina Veresmortean, Padmanava Pradhan, Lijia Yang, Barbara Zajc Org Lett. 2018 Jun 15;20(12):3574-3578. doi: 10.1021/acs.orglett.8b01358. Epub 2018 Jun 1.
Diastereoselective fluorination of N-Boc ( R)- and ( S)-2,2-dimethyl-4-((arylsulfonyl)methyl)oxazolidines and a previously unknown diastereoselective epimerization at the fluorine-bearing carbon atom α to the sulfone was realized. Diastereoselectivities of both reactions were excellent for benzothiazolyl sulfones, allowing access to two enantiomerically pure diastereomers from one chiral precursor. To demonstrate synthetic utility, the benzothiazolyl sulfones were converted to diastereomerically pure ( S, S)- and ( R, S)-benzyl sulfones via sulfinate salts and to amino acids. To understand the diastereoselectivities, DFT analysis was performed.
3. Design, synthesis and biological evaluation of glycolamide, glycinamide, and β-amino carbonyl 1,2,4-triazole derivatives as DPP-4 inhibitors
Mao-Tsu Fuh, Ching-Chun Tseng, Sin-Min Li, Shuo-En Tsai, Tsung-Jui Chuang, Chih-Hao Lu, Ya-Chen Yang, Henry J Tsai, Fung Fuh Wong Bioorg Chem. 2021 Sep;114:105049. doi: 10.1016/j.bioorg.2021.105049. Epub 2021 May 31.
Through modification of the skeleton of Sitagliptin and Vildagliptin, we successfully synthesized and built-up four series of 1,2,4-triazole derivatives, containing N,O-disubstituted glycolamide, N,N'-disubstituted glycinamide, β-amino ester, and β-amino amide as linkers, for the development of new dipeptidyl peptidase 4 (DPP-4) inhibitors. The synthetic strategy for glycolamides or glycinamides involved convenient two-steps reaction: functionalized transformation of 2-chloro-N-(2,4,5-triflurophenyl)acetamide 9 (hydroxylation or amination) and esterification or amidation of 1,2,4-triazole-3-carboxylic acid. On the other hand, the one-pot synthesis procedure, including substitution and deprotection, was developed for the preparation of β-amino carbonyl 1,2,4-triazoles from (1H-1,2,4-triazol-3-yl)methanol 12 or (1H-1,2,4-triazol-3-yl)methanamine 13 and Boc-(R)-3-amino-4-(2,4,5-trifluoro-phenyl)-butyric acid 14. All of glycolamides, glycinamides, and β-amino carbonyl 1,2,4-triazoles were also evaluated against DPP-4 inhibitory activity. Based on the SAR study of DPP-4 inhibitory capacity, β-amino ester 5n and β-amino amide 1,2,4-triazoles 6d and 6p possessed the significant inhibition of DPP-4 (IC50 < 51.0 nM), particularly for compound 6d (IC50 = 34.4 nM). The selectivity evaluation indicated compound 5n and 6p had excellent selectivity over QPP, DPP-8, and DPP-9. In addition, the docking results revealed compounds 5n and 6p provided stronger π-π stacking interaction with residue Phe357 than 1,5-disubstituted 1,2,4-triazole 6d and Sitagliptin 1. In summary, compounds 5n and 6p could be promising lead compounds for further development of DPP-4 inhibitor.
