Pepstatin was demonsrate to be a strong inhibitors of aspartic acid proteinases such as pepsin, renin, and cathepsin D. It contains the novel amino acid statine, (3S,4S)-4- amino-3-hydroxy-6-methylheptanoic acid, which has wide applications in the design and synthesis of inhibitors of asparyl protease, a key enzyme in the renin-angiotensin system, and HIV protease^[1]. It has been accepted that these 4-amino acids are reconized to mimic the transition state structure of substrtate when interacting with an enzyme and only the 3-hydroxy 4- amino acids of the syn configuration can generally adopt a suitable conformation^[2]. Since 1970s, many research groups have used statine as lead compoud, and given modification of the C-terminus and N-terminus.

In 1993, Hui and co-workers reported that the more bulky the aromatic side chain, the more potent the inhibitors was^[3]. Zuos experimental results revealed some important sitea, where steric, electrostatic and hydrophobic modifications would significantly affect the bioactivities of the compounds^[4]. This study we have introduced new groups, such as ferrocenyl group, 3-amino-2-chloropyridine, 2-hydroxybenzoic acid, 4-methy-3-amino-2-chloropyridine, and so on into target compouds. Then we will disclose some relationships between structures and bioactivities.  

References

1 Rich, D. H.; Sun, E. T.; Boparai, A. S.; J.Org.Chem., 1978, 43, 3624-3626.

2 Jia, L-Q.; Jiang, H-F. Guangzhou Chem (in Chinese). 1998, 4, 56-64.

3 Hui, K. Y.; Hermann, R. B.; Manetta, H. J.; et. al. FEBS. Lett. 1993, 327, 355-360.

4 Zuo, Z.; Luo, X.; Zhu, W.; et. al. Bioorg. Med. Chem. 2005, 13, 2121-2131.