Diversity-modification,Structure-anticancer Activity Relationships Of 1-O-acetylbritannilactone And Total Synthesis Of MPC1001/F

Natural products have proven to be valuable sources for the identification of new drugs,and they have been paid close attention for their combination with the targets due to natural selection.Some natural products can be used directly in disease treatment.However,their extremely low natural abundance means that the total synthesis of these compounds is very effective in their supply.Some may have unique but moderate biological activities or even side effects.Then the chemical modification of natural products is very important for the drug development.During the history of organic and pharmaceutical chemistry,a variety of distinctive synthesis strategies have been developed,including Target-Oriented Synthesis(TOS),Diversity-Oriented Synthesis(DOS)et al.In this thesis,we are eagaged in the synthesis and modification of natural products under the guidance of DOS and TOS.The main results are as follows:1.The isolation,modification,SAR analysis and the mechanism of plant-derived 1-O-acetylbritannilactone under the guidance of DOS.(1)1-O-acetylbritannilactone(ABL),a natural product with potent anticancer activity in vitro,was isolated from flowers of the medicinal plant Inula britannica,and 89 analogues of the natural product 1-O-acetylbritannilactone were prepared.Among them,88 are new anlogues.(2)The derivatives were evaluated for in vitro cytotoxic activities by using SRB assay.SAR analysis indicated as follows:a)The esterification of C6-OH(enhanced lipophilicity)and a-methylene-y-lactone functionalities play important roles in conferring cytotoxicity.Among the tested compounds,the one bearing a lauroyl group at the C6-OH position 2.2c displayed the most potent in vitro cytotoxic activity(HCT116,IC50 2.91μM),which 12 times more than ABL(HCT116,IC50 36.10 μM)and comparable with etoposide(HCT116,IC50 2.13 μM),indicating that 12 carbon chains may just be combined with protein pocket.The activity of the aromatic esterification product has also been improved,but the change of the substituent on the aromatic ring has no significant effect on the activity.b)The Michael addition adducts of the a-methylene of OABL lost the anticancer potential.The activity of this class of natural products may related to the covalent adduct formation with important cellular targets.c)The triazole derivatives at C9 have no significant effect on the activity.d)The activity of the analogues at C14 is significantly improved.(3)Cell cycle distribution analysis showed a clear block of cells in G2/M phase.Western blot analysis showed the presence of cleaved caspase-3 which indicated the processing of procaspase-3 and induction of apoptosis.We also tested p53 expression and DNA damage,mRNA expression of p53 target genes,anticancer activity of ABL-L on the p53 knockdown cells.All the data indicated the esterification product causes DNA damage to induce p53 transcription.Activated p53 initiates cell apoptosis through death receptors pathways and mitochondrial pathway.2.Synthetic studies toward a macrolide natural product MPC1001 which shows great potential of anti-prostate cancer activity and triketopiperazine MPC1001F under the guidance of TOS.(1)We completed the construction of MPC1001 BC rings.Based on a three-component reaction,the MPC1001 BC rings was constructed in four steps in which a sulfur-stabilized carbanion cyclized onto the terminal ester was included.(2)We also synthesized the MPC1001F BC rings which is the only synthetic representative of the natural bicyclic sulfide-bearing piperazinetrione system.(3)Then we developed and optimized five synthetic routes to the AB ring systm.Excluding two of these routes,now there are three routes that are more feasible.(4)During the synthesis of MPC1001,we designed and synthesized the nucleophilic sulfur reagent t-BuPh2SiOCH2SH and t-BuMe2SiOCH2SH.The silicon protecting group can be removed under mild conditions.In conclusion,the study on the separation,chemical modification and SAR analysis of the highly-active ingredient in the traditional Chinese medicine Inula britannica established a solid foundation for the development and utilization of sesquiterpene lactone.The development of the synthetic routes to the MPC1001 and MPC1001F BC and AB ring systems has made constructive progress towards the total synthesis of MPC1001 series compounds and research on the activity of MPC1001 series.