Synthesis And Anticancer Activity Study Of Bioactive Natural Products And Their Derivatives

Bisbibenzyls are a series of phenolic natural products that are found exclusively in bryophytes. These natural products exhibite a variety of biological activities, including 5-lipoxygenase, cyclooxygenase and calmodulin inhibitory effects, and antifungal, antimicrobial, antioxidative, muscle-relaxing, and cytotoxic activities. To date, more than 100 types of bisbibenzyl with excellent biological activity have been discovered from the liverworts and some of them could be the prospective leading comound for the drug discovery. Total synthesis and preparation of derivatives of bisbibenzyls with excellent activity is a good way to develop novel drug.Resveratrol, with the sturcture similar to bisbibenzyl, is a natural occuring phytotoxin wide spread in continental plant. Resveratrol was found to exhibite versatile biological activities, such as anti-aging, anticancer, cardioprotective, chemopreventive activities. Within the past decade, it has become increasing clear that resveratrol could target on cycloxygenase, lipoxygenase, nuclear factor kappa B, quinone reaductase, ornithine decarboxylase and aromatase. However, this multi-target property of resveratrol lead to the lack of selectivity and potency, and it is very difficult to pinpoint which target is most important for the treatment of a given disease state. The broad-spectrum of activities exhibited by resveratrol can lead to side effects as well. One possible solution to these various problems is to develop resveratrol analogues that exhibit selectivity for only one target with greater potency.The macrocyclic bisbibenzyl dihydroptychantol A (DHA) was synthesized and showed significant multidrug resistance (MDR) reversing activity in chemoresistant cancer cells. In an attempt to discover more potent MDR reversal agents for efficient cancer chemotherapy, DHA derivatives with thiazole rings were designed and synthesized, and their cytotoxicities and MDR reversal activities were evaluated in adriamycin-resistant K562/A02, vincristine-resistant KB/VCR and their parental cells by MTT assays. Among the tested compouds, the intermediate 20 and the analogues 22,23, and 24 showed potent MDR reversal activities and increased vincristine cytotoxicity in KB/VCR cells, with the reversal fold ranges from 10.58 to 13.81 (10μM), which is stronger than the natural product DHA (RF=3.25). The molecular modeling study reveals the possible binding mode of P-gp with DHA and it's derivatives, which could direct the structure optimization in the further.The macrocyclic bisbibenzyl marchantin C (MC), a potent microtubulin inhibitor, was synthesized and 24 analogues with various amount of hydroxyl group and different substitutive mode on the phenyl ring were prepared. The cytotoxic activity of 8 phenolic compounds was tested by MTT method. Most analogues exhibite more potent cytotoxicity than marchantin C. The IC50 value of compound 36 on U2OS and EYFP is 12.46 and 12.41μM, respectively; and the IC50 value of compound 38 is 16.62μM and 11.71μM, respectively. Both compounds are much more potent than marchantin C.A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The design of the new compounds was guided by molecular modeling based on human aromatase (PDB 3eqm). Compounds 35,104 and 106 were shown to be potent aromatase inhibitors (IC50 values 0.15μM,63.3 nM and 40.3 nM, respectively) with inhibitory activity greater than that of resveratrol (IC50 80μM). In addition to aromatase inhibitory activity, compounds 35 and 47 also displayed potent QR2 inhibitory activity (IC501.7 μM and 0.27μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism QR2 inhibition. The initial biological investigations suggest that these compounds and their analogues merit further investigation as potential chemopreventive agents.