Structural Modification And Hydroxyhalogenation Of Chromen-2-ones With Anti-HIV 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 DCK (2),4-methyl-DCK (11) and 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 bio-molecule(s). To this end, a new series of DCK analogs, namely 7-carbon-and 7-carbonyl-DCK derivatives (28a-c) and 4,8,8-trimethyl-9,10-dihydrobenzo[h]chromene-2,7-dione derivatives (29) 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 crucial to the activity. As a continuous effort towards the development of this type of potential anti-HIV drugs, three new series of analogs of 28b-c and 29, in which two crucial bulky camphanoyl esters were replaced with more stable amides 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 9,10-disubstituents of 28b-c and 29 on their anti-HIV activity and exploring candidate drug suitable for further development.The designed target compounds of 7,8,9,10-tetrahydrobenzo[h]chromen-2-one, 4,8,8-thimethyl-7,8,9,10-tetrahydrobenzo[h]chromen-2-one and 4,8,8-thimethyl-9,10-dihydrobenzo[h]chromen-2,7-dione were synthesized by using 1-naphthol as the starting material. Totally 103 compounds were obtained and 37 of them are novel whose structures were confirmed by various spectral analyses, including 1H NMR, 13C NMR and mass spectra. There are 13 target compounds among them and the structure of which were shown as follows. The anti-HIV activities of these target compounds were tested in TZM-bl cell with 2-ethyl DCP as a reference compound. The preliminary bioassay data indicated that both compounds 89a and 102 demonstrated potent anti-HIV activity, with Inhibition= 47.26% and EC50= 1.47?M, IC50= 20.09?M, TI= 37.90, respectively. The further bioassay on the end points of anti-HIV activities of these 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 preliminary bioassay results suggested that the target compounds with replacement of 9,10-dicamphanoyl by 4-methylphenylsulfonamido respectively demonstrated obvious anti-HIV activities, which suggests that 9,10-dicamphanoyl in these compounds is not the necessity for anti-HIV effect and can be substituted by other bulky groups. As 4-methylphenylsulfonamido is more stable and less inclined to hydrolyze than the camphanoyl esters, the compounds with 4-methylphenylsulfonamido groups might show improved properties in the respect of metabolism, drug resistance and bioavailability in vivo.(2) The activities of compounds with?configurations at 9,10-disubstituents were more potent than those with a configurations which further indicated that the configuration of 9,10-chiral carbon has great effect on the activities of compounds and this result is in accordance with our previous research.(3) The 9-halo-10-camphanoyl-4,8,8-thimethyl-7,8,9,10-tetrahydrobenzo[h]chromen-2-one analogs exhibited certain anti-HIV activities. This result indicated that the substitution of bulky camphanoyl group by suitable groups at 9-position was favorable to the activity and the substitution of camphanoyl group at 10-position was more crucial to the anti-HIV activity.(4) The activities of 4,8,8-thimethyl-7,8,9,10-tetrahydrobenzo[h]chromen-2-one analogs were better than those of 4-methyl-7,8,9,10-tetrahydrobenzo[h]chromen-2-one derivatives, which was in accordance with the previous results obtained in our research group.The SAR results mentioned above will undoubtedly be helpful in finding new class of anti-HIV compounds with stable metabolism, improved bioavailability, less drug resistance and further optimization of anti-HIV activities of this type of compounds.During the synthesis of the target molecules, we also disclosed a series of interesting chemical reaction features, especially the discovery of an efficient method for chlorohydroxylation and bromohydroxylation of olefins, which has been established by using chloramine T trihydrate, 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), or N-bromoacetamide (AcNHBr) as the halogen source in combination with N-tosyl-L-threonine (NTsLT) as the acidic additive. The significant advantages offered by this method include simple manipulation, fast reaction and mild conditions, as well as wide adaptability of substrates with high yield and excellent regio- and stereoselectivity of product, and thus providing a better and practical alternative to the existing procedures for the synthesis of vicinal halohydrins.The studies of synthetic methodology provided valuable information on the synthesis and chemical properties of these new types of heterocyclic compounds.