Dcp Derivatives Were The Design Of The Anti-hiv Activity And Synthesis

Suksdorfin (1), isolated from the fruit of Lomatium Suksdorfii, has an angular pyranocoumarin skeleton with promising anti-HIV activity. Structural modifications of 1 gave 4-methyl-DCK (11, EC50=0.0059μM, TI>6660) and 2-ethyl-DCP(16, EC50=0.00032μM, TI=116200), which demonstrated extremely potent inhibitory activity against HIV-1 replication.2-Ethyl-DCP with higher anti-HIV activity against non-drug-resistant strain also showed potent activity against multiple reverse transcriptase (RT) inhibitor-resistant strain (EC50=0.06μM, TI=718).In our previous research,2’α-monomethyl-DCK showed significant anti-HIV activity, while 2’P-monomethyl-DCK exhibited low activity, even no activity. These results implied that 2’-position of DCK analogs was intimately related with the binding site of virus receptor, there is probably only a small space at a orientation. Furthermore, the anti-HIV activity of 1’-S-DCKs were higher than the 1’-O-DCKs. 4-Methyl-1’-thia-DCK exhibited moderate potency against drug resistant HIV-1 RTMDR1 (EC50=2.25μM, TI> 12.4), which was not sensitive to 1’-O-DCK derivatives. This suggested that 1’-sulfur atom instead of 1’-oxygen atom in DCK may be favorable for improving anti-HIV activity against multiple reverse transcriptase (RT) inhibitor-resistant strain.Combining the research results of DCK derivatives and the SAR knowledge of DCK accumulated through the previous structural modifications, a series of novel DCP analogues,2’-monomethyl-2-ethyl-DCP (33a,33b),2’-monomethyl-2-ethyl-1’-thia-DCP (37a,37b,37c) and 2’,2’-dimethyl-2-ethyl-1’-thia-DCP (41a,41b), were designed and synthesized in order to explore their anti-HIV activity, especially the activity against multi-RT inhibitor-resistant HIV-1 strains.In this thesis research, using m-dihydroxybenzene as starting material, through three synthetic routes, three types of new anti-HIV inhibitors were designed, synthesized and evaluated for anti-HIV activity. The structure and activity relationships (SAR) were also summarized by the data from the bioassay. The structures of 24 new compounds including 7 target compounds were confirmed by various spectral analyses, including 1H NMR,13C NMR and mass spectra. From the feedback bioassay data, the anti-HIV activity of three target compounds (33a,37a,41a) with 2’α-monomethyl-3’,4’-βcamphanoyl ester configuration or 2’,2’-dimethyl-3’,4’-βcamphanoyl ester configuration were higher than the reference compound 2-ethyl-DCP, which coincided with the SAR results of DCK derivatives accumulated through the previous research.