NOVEL HIV-1 PROTEASE INHIBITOR PRODRUGS

Yoshio Hamada

Faculty of Frontiers of Innovative Research in Science and Technology, Konan University, Hyogo, Japan

Abstract

The selective cleavage of an amide bond at room temperature or physiological conditions will be a powerful tool for life science and medicinal chemistry. However, the cleavage of amide bonds requires considerable energy, whereas ester bonds can be easily cleaved. The amide bond cleavage reactions are known in nature; for example, a protein, intein, undergoes protein splicing that involves an amide bond cleavage. To develop an amide bond cleavage reaction, we investigated the decomposition reaction arginine methyl ester reported by Photaki et al. In this reaction, the guanidino group of an arginine methyl ester attacks the ester carbonyl carbon of another arginine methyl ester, forming an arginine dimer. Next, the N-terminal amino group of the dimer attacks the guanidino-carbon within the molecule, forming a heterocyclic compound and ornithine methyl ester. We assumed that the driving force of this decomposition reaction is the release of the heterocyclic compound that is stabilized because of a conjugate structure. Hence, we designed some novel prodrugs that release a heterocyclic compound. These prodrugs could release the parent drugs with an amino bond under physiological condition. In this study, we designed and synthesized a series of HIV-1 protease inhibitor prodrugs using our prodrug strategy.

Keywords: Prodrug, HIV-1 protease inhibitor, phenytoin, sulfa drug.