The Structural Transformation Of The Anti-hiv Coumarin Compounds And Biological Activity

Suksdorfin (1), a natural product isolated from the fruit of Lomatium Suksdorfii, has an angular pyranocoumarin skeleton with interesting biological properties, especially its anti-HIV activity. Structural modification of 1 yielded 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK,2),4-methyl-DCK (11) and (3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP), which demonstrated extremely potent inhibitory activity against HIV-1 replication in H9 lymphocytic cells.The mechanistic studies indicated that HIV-1 RT is possibly the target of DCK and DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity. In contrast, DCK did not significantly affect the RNA-dependent DNA polymerase activity. Due to its unique mode of action, DCK and its derivatives could be used to functionally dissect HIV-1 RT and might have the potential to be clinically useful. Accordingly, selected modifications on DCK skeleton are highly desirable in order to identify the pharmacophores in this class of potent anti-HIV agents and explore the structural aspect of the target biomolecule(s). To this end, a series of DCK analogs, namely 7-carbon- and 7-carbonyl-DCK derivatives (28a-c) and five-membered-C-ring DCK analogs (30) were synthesized previously in our group. The anti-HIV bioassay data indicated that these DCK analogs also exhibited potent inhibitory effects on HIV-1 replication in H9 lymphocytes and two bulky camphanoyl ester groups were important for the activity. As a continuous effort towards the development of this type of potential anti-HIV drugs, two new series of analogs of 28a and 30, in which two bulky camphanoyl esters were replaced with more stable amides, ethers or halogens, were designed based on the principle of bioisomerism. The studies on the synthesis and the SAR of these analogs might provide useful information for understanding the impact of two camphanoyl ester groups of 28a and 30 on their anti-HIV activity and exploring candidate drug suitable for further development.The synthesis of designed 7,8,9,10-tetrahydrobenzo[h]chromen-2-one analogs were accomplished starting from 1-naphthol and the target compounds of 4,7,7-thimethylcyclopenta[h]chromen-2-one were synthesized by using 1-bromo-2-methoxybenzene as the starting material. Totally 98 compounds were obtained and 49 of them are novel whose structures were confirmed by various spectral analyses, including 1H NMR,13C NMR and mass spectra. The anti-HIV activities of these compounds and some of their synthetic intermediates were tested in TZM-bl cells acutely infected by NL4-3 virus with 2-ethyl DCP as a reference compound. The preliminary bioassay data indicated that compounds 118 and 114 demonstrated obvious anti-HIV activity, with IC50>16.84μM, EC50=0.878μM, TI>19.23 and IC50>24.15μM, EC50=1.47μM, TI>16.43, respectively. Compound 76 exhibited certain anti-HIV activity with IC50=9.71μM, EC50=3.23μM, TI=2.95. The further bioassay on the end points of anti-HIV activities of other compounds is undergoing. At this stage, the following new concepts can be gained on the basis of the information attained from these preliminary bioassay results:(1) The substitution of bulky groups (eg. p-toluenesulfonyl) at 10-position of six-membered-C-ring or 9-position of five-membered-C-ring target molecules is crucial for the anti-HIV activity, whereas the substitution at 9-position of six-membered-C-ring or 8-position of five-membered-C-ring target molecules is less important.(2) Most of the compounds which contained halogen atoms demonstrated certain anti-HIV activity.(3) Both the ether analogs of 28a and 30 showed certain anti-HIV activity, which further demonstrated the importance of large groups at 10-position or 9-position once again.The SAR results mentioned above will undoubtedly be helpful in further optimization of anti-HIV activities of this class of compounds and exploring the structure of receptor biomolecule.During the synthesis of the target molecules, we also disclosed a series of interesting chemical reaction features, especially the discovery of novel Friedel-Crafts reaction with alkane as the alkylating component via sp3 C-H bond activation on the basis of carbocation relay, which provided a new scope of alkylating reagents for classical F-C reaction.The studies of synthetic methodology provided valuable information on the synthesis and chemical properties of these new types of heterocyclic compounds.