抗HIV香豆素的结构修饰与合成资料.ppt

four coumarin derivatives, calanolides A and B and inophyllums B and P, isolated from Calophyllum lanigerum and Calophyllum inophyllum Linn, respectively, were reported as potent anti-HIV agents. Their anti-HIV activity is due to inhibition of the HIV-1 reverse transcriptase. the anti-HIV mechanisms of these tetracyclic coumarins and of the tricyclic compounds Suksdorfin and DCK are different. The anti-HIV activity of compound DCK is also about 2 orders of magnitude greater than that reported for the tetracyclic coumarins. DCK is a nanomolar inhibitor of both primary clinical and drug-resistant HIV-1 isolates, but has no effect on HIV-2 or SIV. Compared to approved HIV drugs, it has a novel mechanism of action, as it blocks RT, but at a later step than the FDA-approved RT inhibitors. (3) Methyl or other aliphatic substitutions on the DCK C-3, C-4, and C-5 are favorable for anti-HIV activity against the non-drug resistant strain, whereas aromatic substituents and 6-substitution are not. The DCK C-3 can tolerate polar but not charged or electron withdrawing substituents. (4) The bioisosteric isomers, thio-DCK and DCK lactam retain activity. (5) The positional isomer, DCP, is even more promising since most DCP analogs are active against a multiple RT inhibitor resistant strain, while most DCK derivatives are ineffective against this drug-resistant HIV-1 strain. (6) An appropriate alkyl substituent at position 2 is critical for the anti-HIV activity of DCP analogs against both non-drug resistant and multi-RT resistant viral strains. In addition, most 2-substituted DCP analogs are less toxic to the cells compared with DCP. Low water solubility, less potency against drug resistant HIV strains, and fast metabolism are three main obstacles that limit the development of DCK analogs. Further analog design is likely to use DCP as a new lead to increase the potency against drug resistant viral strains and improve water solubility, and