Hiv Integrase Inhibitors Interface And Estrogen Agonists Design, Synthesis And Biological Activity Research

The dissertation contains two chapters.Chapter 1 regards the design, synthesis and biological evaluation of inhibitors targeting the interaction between integrase and cellular LEDGF/p75. In view of prone mutations associated with HIV-1 drug resistance, discovering anti-HIV-1 drugs with new pharmacological mechanisms are the hot topic today. HIV intergrase (HIV-IN) is one of the three key enzymes in HIV-1 life cycle, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration of viral-DNA into host chromosome mediated by HIV-IN. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. Based on active conformation of the lead compound D77 discovered previously by us, in-house database, consisting of approximately 500 active compounds, was screened. A N-arylallylidene-substituted phenylhydrazone compound (A-1) was identified as inhibitor of interaction between HIV-IN and LEDGF/p75 in Alphascreen assay (ICso= 45.99±5.02μM). To improve the activity of A-1, totally, twenty-one target molecules (A-2-A-22) were designed, synthesized, and evaluated by Alphascreen assay. The results indicated that three compounds (A-9:IC50= 8.03±1.77μM, A-12:IC50= 15.62±0.41μM, and A-19:IC50= 7.23±0.63μM) could potently inhibit the interaction between HIV-IN and LEDGF/p75. The activity of the most potent inhibitor (A-19) is～6 times more potent than that of the lead compound (A-1). On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of class A compound, which give some valuable clues for further design of inhibitors targeting HIV-1-IN interaction with LEDGF/p75, and might supply useful structural information for further anti-HIV agent discovery.Chapter 2 concerns the design, synthesis and biological evaluation of estrogen receptor (ER) selective agonists. The ER is a member of nuclear receptors superfamily, plays critical roles in cancer, metabolic diseases, etc, and regarded as an important drug target. ER has ERαand ERβtwo subtypes, and both subtypes have different tissue distributions and functions in the human body. Therefore, it is important to seek novel subtype selective ligands. Based on structure of the compound JB052, a ER selective antagonist, discovered previously by us, in order to obtain the novel anologs of JB052, scaffold hopping was performed on the basis of pharmacophore of JB052. A class of molecule (B series) featuring the (Z)-2-(4-hydroxybenzylidene)-6-hydroxybenzo[b]thiophen-3(2H)-one framework was discovered by adding a cycle structure into JB052. The new B series compounds were confirmed as potent ER ligand using molecular docking. Totally, four target molecules (B-1～B-4) were designed, synthesized, and evaluated by yeast two-hybrid technology based assay. The results indicated that four compounds could potently activate ERβ, two compounds (B-1 and B-2) activate ERβin nanomolar level (EC50= 52.3 nM and 38.7 nM), and three compounds (B-1～B-3) shows potent ERa agonistic activities (EC50= 0.165～0.731μM). Interestingly, none of compounds was observed for ER antagonistic activities, and the agonistic activity of compound B-4 was also observed for ERβspecificity over ERα(β:EC50 = 7.81μM/α:EC50= NA). On the basis of biological results, we can deduce the preliminary structure-activity relationships (SARs) of class B compound, which give some valuable clues for further design of ER selective agonists.