1. Renin inhibitors. Substitution of the leucyl residues of Leu-Leu-Val-Phe-OCH3 with 3-amino-2-hydroxy-5-methylhexanoic acid
R L Johnson J Med Chem. 1982 May;25(5):605-10. doi: 10.1021/jm00347a024.
The 2S,3S and 2R,3S diastereoisomers of the hydroxy amino acid 3-amino-2-hydroxy-5-methylhexanoic acid (AHMHA) were synthesized and substituted for the leucyl residues of Leu-Leu-Val-Phe-OCH3 to yield the following analogues: AHMHA-Leu-Val-Phe-OCH3, AHMHA-Val-Phe-OCH3, and Leu-AHMHA-Val-Phe-OCH3. These analogues were tested in vitro for their ability to inhibit human amniotic renin. All of the analogues were found to inhibit renin to some extent with inhibitory constants in the range of 10(-3) to 10(-4) M. The analogues AHMHA-Leu-Val-Phe-OCH3 and AHMHA-Val-Phe-OCH3 exhibited competitive inhibition when the 2S,3S isomer of AHMHA was employed and noncompetitive kinetics when the 2R,3S isomer of AHMHA was used. For the Leu-AHMHA-Val-Phe-OCH3 analogues, competitive kinetics were observed regardless of the isomer of AHMHA employed. These latter analogues also proved to be the most active in the above series.
2. Analysis of amide bond formation with an alpha-hydroxy-beta-amino acid derivative, 3-amino-2-hydroxy-4-phenylbutanoic acid, as an acyl component: byproduction of homobislactone
Y Hayashi, Y Kinoshita, K Hidaka, A Kiso, H Uchibori, T Kimura, Y Kiso J Org Chem. 2001 Aug 10;66(16):5537-44. doi: 10.1021/jo010233o.
In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.
3. Structure-activity relationships of HIV-1 PR inhibitors containing AHPBA
M Sakurai, S Higashida, M Sugano, T Komai, R Yagi, Y Ozawa, H Handa, T Nishigaki, Y Yabe Bioorg Med Chem. 1994 Aug;2(8):807-25. doi: 10.1016/s0968-0896(00)82181-1.
A series of Human Immunodeficiency Virus type-1 protease (HIV-1 PR) inhibitors that contain 3-amino-2-hydroxy-4-phenylbutanoic acid (AHPBA) at the scission site of the substrate were prepared and evaluated for their inhibitory activity. Preliminary studies on the chain length of inhibitors and the hydroxyl configuration of AHPBA indicated that small (2S,3S)-derivatives, composed of the regions between the P3 and P2' sites, showed enough inhibitory activity toward HIV-1 PR to become prototypes for further structural modification. Systematic replacement at the sites from P3 to P2' revealed that some bicyclic heteroarylcarbonyl derivatives possessed strong potency and good enzyme selectivity.
