1. Enantiospecific and Stereoselective Synthesis of Polyhydroxylated Pyrrolidines and Indolizidines from trans-4-Hydroxy-L-proline
María-Jesús Blanco, F. Javier Sardina J Org Chem. 1996 Jul 12;61(14):4748-4755. doi: 10.1021/jo9604245.
We have developed a short, efficient, and stereoselective synthesis of polyhydroxylated pyrrolidine and indolizidine glycosidase inhibitors starting from 4-hydroxy-L-proline. The regio- and stereoselective hydroxylation of an N-Pf-4-oxoproline enolate and the stereoselective reduction of the resulting keto alcohol allowed us to introduce the cis diol present in the target compounds. The different side chains needed to complete the syntheses of the target compounds were introduced by reduction of the ester group of a substituted proline or by reaction of organolithium or organomagnesium reagents with the same group followed by stereoselective reduction of the resulting ketones. Hydrogenolysis of the alcohols thus obtained gave the hydrochlorides of the desired pyrrolidine glycosidase inhibitors, which were obtained in nine steps in overall yields greater than 50%. The indolizidine glycosidase inhibitor 8-epi-swainsonine was also prepared using this approach.
2. Studies on the mechanism of action of cetraxate [4'-(2-carboxyethyl)phenyl trans-4-aminomethyl cyclohexanecarboxylate hydrochloride], a new anti-ulcer agent
Y Suzuki, M Ito, Y Sudo Jpn J Pharmacol. 1979 Dec;29(6):829-38. doi: 10.1254/jjp.29.829.
To elucidate mechanisms involved in the anti-ulcer action of cetraxate, the effects of this agent on the ulcer index (UI), fibrinolytic activity (FA) and contents of several connective tissue components in ulcer tissue were examined using aspirin- and acetic acid ulcers in rats. In aspirin ulcer, cetraxate (100 and 300 mg/kg p.o.), like tranexamic acid (500 mg/kg p.o.), epsilon-aminocaproic acid (500 mg/kg p.o.) and gefarnate (200 mg/kg p.o.), inhibited both the UI and FA. However, aluminum sucrose sulfate (1000 mg/kg p.o.) was effective only against the UI and L-glutamine (500 mg/kg p.o.) failed to inhibit both parameters. In acetic acid ulcer, following oral, daily X either 5 or 8 administrations, cetraxate (200 and 300 mg/kg), gefarnate (200 mg/kg), aluminum sucrose sulfate (1000 mg/kg) and L-glutamine (500 mg/kg) were effective on both the UI and FA. Tranexamic acid (500 mg/kg) and epsilon-aminocaproic acid (500 mg/kg) were ineffective on the UI, although both agents inhibited FA. In acetic acid ulcer, cetraxate induced increases in hexosamine and uronic acid, that is, acid mucopolysaccharides (AMPS), especially chondroitin sulfate A and -C, whereas L-glutamine and aluminum sucrose sulfate resulted in increases in hexosamine and sialic acid, that is, glycoproteins. From these results, cetraxate may mainly accelerate the ulcer healing by increasing AMPS in ulcer tissue. Moreover, the local anti-FA property of this agent may be also beneficial in treating bleeding ulcers.
3. Inhibition of angiotensin converting enzyme by L-alanyl-4 or 5-substituted-L-prolines and their N alpha-phosphoryl-derivatives
E N Alexandrou, M Liakopoulou-Kyriakides Biochem Int. 1990;21(2):271-8.
A series of L-alanyl-4 or 5-substituted L-prolines, such as L-alanyl-L-thiazolidine-4-carboxylic acid, L-alanyl-5-oxo-L-proline, L-alanyl-trans-4-hydroxy-L-proline and L-alanyl-cis-4-hydroxy-L-proline as well as their corresponding N alpha-phosphoryl derivatives, were synthesized and studied for inhibition against angiotensin converting enzyme. Furanacryloyl-phenylalanyl-glycyl-glycine was used as substrate in 50 mM Tris hydrochloride buffer at pH 7.5 containing 1 microM zinc acetate. N alpha-Phosphoryl-L-alanyl-L-thiazolidine-4-carboxylic acid and N alpha-phosphoryl-L-alanyl-trans-4-hydroxy-L-proline competitively inhibit angiotensin converting enzyme with Ki values of 68 microM and 89.3 microM, respectively. Smaller inhibition against angiotensin converting enzyme was obtained with the rest of compounds studied here.
