Design, Synthesis And Biological Activity Of The New Class Of Compounds In .seco-dck/dcp And Rimexolone Synthesis Method Study

This dissertation has two parts of research as followed:Design, Synthesis of Novel Seco-DCK/DCP Compounds and HIV Inhibitory ActivitySuksdorfin (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 4-methyl-DCK (11) and 2-ethyl-DCP (20), which demonstrated extremely potent inhibitory activity against HIV-1 replication.The recent mechanistic studies of pharmacological action indicated that HIV-1 RT is possibly the target of DCK and DCK is a special 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/DCP and their derivatives could be used to functionally dissect HIV-1 RT and might have the potential to be clinically useful. Accordingly, selected modifications on DCK/DCP skeletons 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 variety of novel DCK analogs containing N,N-, O,N-, N,O-, O,S-, S,O-or O,C-by displacing the 0,0 atoms in the DCK skeleton were synthesized previously in our group. The structural modifications of 4-methyl-DCK by replacing the ring oxygen atom of DCK with a sulfur atom (23d and 24b) demonstrated that these analogs also exhibited potent inhibitory effects on HIV-1 replication in H9 lymphocytes. In order to exploring the effect of intact A ring and C ring to the activity, a series of new Seco-DCK analogs were designed and synthesized in our group. The simplest effective skeleton moiety and necessary pharmacophores were in searching of by cleavaging different carbon bond of A ring or C ring. Among these new analogs, compound 31c exhibits excellent anti-HIV activity. Seco-DCK analog is a new breakthrough in the research on anti-HIV drug DCK/DCPs which is a novel HIV inhibitor. Compared with DCK/DCPs, compound 31c has a less complex structure, fewer hydrogen-bond acceptors, and a reduced Log P value. Therefore, it is likely to exhibit better pharmaceutical properties, and appears to be a promising new lead for further development as an anti-HIV candidate.On the basis of these results, two series of novel Seco-DCK/DCP sulfuric derivatives (36 and 37) were designed, combining the SAR knowledge accumulated through the former structural modification. The studies on the SAR of these compounds might provide the useful information for understanding the impact of sulfur atom of Seco-DCK/DCP on the anti-HIV activity. Presently, all of the DCK/DCP analogs are camphanoyl esters. Considering esters are not stable in the metabolic process in vivo and will be hydrolyzed quickly. A series of novel Seco-DCP camphanoyl ether derivatives (38) were designed here in order to explore the impact of camphanoyl ester on the anti-HIV activity, especially on the activity against multi-RT inhibitor-resistant HIV-1 strains. Moreover, all of the target molecules are new heterocyclic compounds and their preparation remains a challenge from the viewpoint of synthetic chemistry. This study has potential scientific significance by accumulating new knowledge and providing a synthetic method of such novel heterocyclic skeletons.The syntheses of the designed compounds 36 were accomplished starting from m-dihydroxybenzene. A synthetic route of 1-thio-4-hydroxy-chromones starting from m-dihydroxybenzene was established with the total yield of 13.69%. Additionally, the reagents used were conventional and the operations were convenient in this route, which is important in expanding research on Seco-1-S-DCK/DCPs.In the syntheses of Seco-7-S-DCP derivatives, two synthetic routes were explored starting from 2,6-dihydroxytoluene and m-dihydroxybenzene respectively. During the first route, derivatives with 7-sulfur atom were obtained successfully. Due to the special reactive nature of sulfur atom, the subsequent synthesis was hampered and the designed Seco-7-S-DCP derivatives were not obtained. In the second route, the precursor of Seco-7-S-DCP derivatives was synthezed successfully and the target compounds will be obtained after enough quantity of precursor are accumulated.The syntheses of the designed Seco-DCP camphanoyl ether derivatives (38) were accomplished starting from 2,6-dihydroxytoluene. The structures of all all the target analogs were confirmed with 1H NMR and mass spectra.All of the the target analogs and most of the novel intermediate compounds were tested in TZM-bl cells with 2-ethyl-DCP as a reference compound. The bioassay of the most 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 Seco-DCP camphanoyl ether showed good antiviral activity. Seco-DCP camphanoyl ether derivatives are more stable than camphanoyl esters and exhibit better pharmaceutical properties.(2) The potency and the activities of analogs 38a,38b and 38c with camphanoyl ether groups were in accord with SAR found previously with the DCK series.(3) Compounds 92 and 93 without camphanoyl ester groups also showed good anti-HIV activities in multiple reverse transcriptase (RT) inhibitor-resistant strain, which indicated that camphanoyl ester were not necessary on the activity against multi-RT inhibitor-resistant HIV-1 strains.These results mentioned above will undoubtedly be helpful in further optimization of anti-HIV activities of this class of compounds, and may provide clues for exploring the structure of receptor biomolecule.During the synthesis of the target molecules, we also disclosed a series of interesting chemical reaction features, which are summarized as follows:(1) During the process of 1-S-A-ring synthetic research, methods in literaties (C.K. Lau et al. J. Org. Chem.1987,52:1690-1673.) as reference, strategies such as 1H NMR,NOEDS,HMBC and X-ray analysis were applied, for the confirmation of the exact structure of the product. The output data reveals discrepancy with the literaties. And that convinces us of the flaw of the reference. Furthermore, we have developed novel theory for explanation of the reaction mechanism.(2) While in the research process of O-aryl dimethylthiocarbamates synthesis, using reagent dimethylthiocarbamonyl chloride, methanol was applied in the reaction system as the solvent, in stead of DMF. As for the modification, the yield increases from 50% to 95.8%, as well as shortened reaction time and simplified operations during the reaction.(3) In the synthesizing 7-S derivatives from 7-O derivatives, by Newman-Kwart Rearrangement reaction, we stumble on a fact that, the compound 91 with benzyl hydroxy will transform into the compound 92 under mild conditions. According to literatures, the Newman-Kwart Rearrangement reaction undertakes usually in high temperature condition, moreover it is rare experience that compounds with benzyl hydroxy will rearrangement under mild conditions. In the reaction system, we also have isolated the unexpended compound 93 and the structure of 93 was elucidated. We carried out serious discussion about the confirmation of the structures of compounds 92 and 93, we have also discussed about the reaction mechanism theory.(4) The effect of the catalyst, inhibitor and temperature on the bromination reaction of 2-ethyl-7-methyloxy-8-methyl-4H-chrom-4-one (98a) was explored. And through condition optimization, we have found an integrate way of preparing the expected key intermediate.Study on the synthetic route of RimexoloneRimexolone is a novel type of glucocorticosteroids; and most of the current chemical synthesis methods are suffering problems such as complicated procedures, low utility consumption, as well as serious pollution. During the study, synthesis of the precursor 16a,21-dimethyl-11β,20-bis(trimethylsiloxy)-pregna-1,4,17(20)-trien-3-one(118), through innovative improvements of the abovementioned methods in literatures, we have apparently improved the reaction yield, eliminated the necessary of toxic regents, and simplified the operation procedures. Here are the most highlighted innovative improvements:(1) 21-Chloride was used as the intermediate, instead of 21-sulfonic ester, in preparing 1,4-dien-11β,17α-dihydroxy-pregna-3,20-dione(114), and higher yield was achieved. Moreover, catalytic dose of NaI was added to the reaction, and Na2S2O4 was used to replace Na2S2O3/NaHSO3. In the iodation-reduction reaction, catalytic dose of NaI was applied, rather than the 2 molar ratio dose mentioned in the literature. As a result of the modification, the reaction was remarkably improved, in aspects of reaction yield, product quality, as well as environment compatibility. One pot reaction has saved us a lot of time and energy.(2) Through multi-conditioned intensive research and theoretical research, we apply relatively inexpensive t-BuOLi rather than LiN(TMS)2 as alkali in the reaction of 21-methylation. Result is that we have completed the 21-methylation reaction in such a relative high efficiency, and optimized the reaction condition, from a demanding -60——65℃, to glacial and saline bath condition. On that basis, we have carried on further study on the modified method, on some other substrates. Results revealed of its applied value, and universality. Taken into consideration of the unique pharmacology of 21-alkyled steroids discovered in recent years, the foundation of this method enables the possibility of SAR study in this field.(3) Using CuCl as the catalyst, we apply CH3MgI to replace the referred (CH3)2Cu(CN)Li in the literature, during the process of 16-methylation. The reaction yield was about the same as referred in the literature.