Synthesis And Biological Evaluation Of Desmosdumotin C Derivatives

Cancer is the major disease which seriously hazard human’s life and health, characterized by uncontrolled cellular growth, tissue damage, invasion and metastases. According to an estimate from the American Cancer Society, a total of1,638,910new cancer cases and577,190deaths from cancer are projected to occur in2012. Although the deaths from cancer have been dropped0.6percent this year, the reduction in overall cancer mortality rate has been disappointing. Currently, cancer is second only to cardiovascular disease as a cause of mortality and is set to become the most common in the near future. Recent progress in cancer drug discovery have been impeded due to severe side effects, development of resistance to the current drug and limited available chemical space, which have fueled high demands for new chemotherapeutic agents with new scaffolds and prompted us to discover new biologically active chemical entities. In this continuing study, we have reported the design and synthesis of novel derivatives of Desmosdumotin C as potential antitumor agents.The preparation of Desmosdumotin C was optimized. Firstly, using2,4,6-trihy-droxyacetophenone as start material, the trimethyl substituted intermediate was prepared at basic condition, and then the crude product was washed by a small amount of methanol and recrystallized with petrol ether and ethyl acetate to afford pure products. This avoid the tedious column chromatography and streamlined the preparation process.. Three synthetic methodologies were designed and accomplished. Firstly, the4,4-Bis(ethylthio)but-3-en-2-one was prepared via2-step synthesis, and then reacted with Desmosdumotin C in methanol in the presence of acetyl chloride. Micheal addition of thiol substituted analogs with Des-C was achieved. Secondly, the4-amino acid amides-benzaldehyde was prepared by Schotten-Baumann reaction condition, and then reacted with (E)-2-(1-hydroxylidene)-5-methoxy-4,6,6-trimethylcyclohex-4-ene-1,3-dione via aldol condensation to afford Des-C derivatives with amide-linked substitute on B-Ring. Thirdly, a Vilsmeier reaction was employed on2,4,6-trihydroxyacetophenone, and then treated with methyl iodide to afford methyl on benzene ring, treated with TMSCHN2to afford O-methylization. Then five benzoyl substituted Des-C compounds were synthesized through aldol condensation reaction.The anti-proliferation evaluation of15compounds using A549, DU145, HCT-8, HL-60, HUVEC and GNM. The activity of compound DC10c was better than that of Des-C, and the activities of eight compounds were comparable to that of Des-C. Limited SAR could be concluded from the results of anti-proliferation of tumor cell:To preserve5,6-structure makes crucial contribution to the anti-proliferation activities; To introduce an amino acid amides on B-ring is good for the increasing activities.