.1. Non-peptide Class Of Human Immunodeficiency Virus Type ¢ñ (hiv-1) Synthesis And Biological Activity Of The Protease Inhibitors. Human Immunodeficiency Virus Type ¢ñ (hiv-1) Reverse Transcriptase Inhibitors Of Natural Products Total Synthesis And Biolo

Human immunodeficiency virus (HIV) is the cause of acquired immuno deficiency syndrome(AIDS), which is one of the most dangerous diseases around the world. Recently, a new target-HIV-1 protease (HIV-1 PR) was found by the improvement of research on the molecular biology about HIV. HIV-1 PR is an aspartic acid protease, which plays an important role in the reproduction process of HIV. Inhibition of HIV-1 PR will cause the production of immature non-infective HIV virons in infected cells. PD099560 is the first non-peptide HIV-1 PR inhibitor (Ki= 1.0μmolL^-1 ). We synthesized 36 new compounds including 28 3-substituted coumarin derivatives (I) (II) and 8 N-substituted phthalimide derivatives (III), which are unknown compovmds, designed on literature references and our research experiences. Their structures were confirmed by ¹H-NMR and elemental analysis. These compounds were tested for anti-HIV-1 PR activities and it were found that compound (12) (32) (45) and (49) have anti-HIV-1 PR activities which IC₅₀ are13, 5,2.1,15μM, respectively. (+)-Calanolide A and (-)-Calanolide B are the most potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT) among the novel class of anti-HIV-1 RT agent dipyranocoumarin derivatives, which were isolated from several tropical plants of Calophyllum lanigerum by the scientists of the American National Cancer Institute (NCI). Our group has explored a total synthesis of (±)-Calanolide A by a four-step reaction sequence in 1995. (+)-Cordatolide A and (+)-Inophyllum B are also natural products isolated from Calophyllum cordato-oblangurn and C..inophyllum, respectively, which contain either a methyl or a phenyl group at the 4-position instead of the n-propyl group in the (+)-Calanolide A. They are potent HIV-1 RT inhibitors too. This dissertaion completes the total synthesis of (±)-Cordatolide A, (±)-Cordatolide B, (±)-Inophyllum B, (±)-Calanolide B and their analogues (±)-11-demethyl- cordatolide A and (±)-11-demethyl-cordatolide B for the purpose of further researching the structure-activity relationships of the target compounds. The structures of these compounds were confirmed by ¹H-NMR, MS, IR and elemental analysis. Meanwhile, we modified greatly the second and the third steps of the former total synthetic route of (±)-Calanolide A, which was published in a previous paper by our research group. The modified procedure was simpler and more convenient while reaction time were shortened remarkably. The yield of this two step procedure and total yield were increased. This dissertation explored and completed the resolution of(±)-Cordatolide A to give (±)-Cordatolide A and (-)-Cordatolide A with [α] _D²⁸=+51.8°and-58.1°, respectively. Moreover, the anti-HIV-1 RT and anti-HIV-1 activities of compounds were tested to evaluate their structure-activity relationships.R₁=n-C₃H₇ R₂=CH₃ R₃=OH R₄=H (±)-Calanolide AR₁=n-C₃H₇ R₂=CH₃ R₃=H R₄=OH (±)-Calanolide BR₁=CH₃ R₂=CH₃ R₃=OH R₄=H (±)-Cordatolide AR₁=CH₃ R₂=CH₃ R₃=H R₄=OH (±)-Cordatolide BR₁=Ph R₂=CH₃ R₃=OH R₄=H (±)-Inophyllum BR₁=CH₃ R₂=H R₃=OH R₄=H (±)-11-demethyl-cordatolide AR₁=CH₃ R₂=H R₃=H R₄=OH (±)-11-demethyl-cordatolide B...