Synthesis And Antitumor Activity Of New Antitumor Derivatives Of Gambogic ACID

Gambogic acid (GA) is the major active component of gamboges, a resin exuded from Garcinia hanburyi Hook f.. Recent studies have demonstrated that GA had potent cytotoxicity against various human cancers, could kill tumor cells selectively, but had no effect on the normal hematopoietic and immune system. In this paper, the structure derivatization, modification, biological activity and the structure-activity relationship of the corresponding compound had been firstly reviewed. Meanwhile, the necessary groups of GA for its antitumor activity are also introduced. Based on those, we conducted such research:the rearrangement and derivatization of GA, their antitumor and antibacterial activity.1. We had placed pyridine salt of GA in different acid conditions to research the changes of the rearrangement reaction of GA over time at80℃. Three major compounds (S2, S3, S4) were generated at1h in the mixture of acetic acid and p-TSA; another compound SI was generated at3h, while S2, S3, S4also exist; and the reaction did not change as the reaction time continued. These compounds were seperated by means of silica gel column chromatography and HPLC, and elucidated by means of spectroscopic methods including1H,13C, DEPT, HSQC, HMBC, NOESY-NMR, ESI-MS and IR.2. The microwave condition can accelerate the rearrangement, so we placed pyridine salt of GA in the mixture of acetic acid and p-TSA for5minutes at80℃under microwave irradiation. From the reaction, we could see that the final products of the condition were the same as the3h at ordinary condition which was mentioned above.3. Due to the big molecular weight and poor water-solubility of GA and its rearrangement products, we planed to derive some groups which contained nitrogen to S1at30-COOH, it also could improve the combination of the compounds and the antiapoptotic protein. In order to invest the function of C9/C10double bond of the rearrangement products, compound S13was synthesized from S11and morpholine through the Michael addition.4. The antitumor activity in vitro of the compounds were evaluated by standard MTT assay. We selected three kinds of tumor cell lines:human lung cancer cells (A549), human colon cancer cells (HCT116) and human breast cancer cells (MDA-MB-231). The results showed that the four kinds of rearrangement products were much better than GA in all three tumor cell lines, the six kinds of derivants of S1were similar to S1in the antitumor activity. To our delight, we got a compound S10with a strong antitumor activity, the IC50(μg/ml) to the three cell lines were0.21、0.066、0.029resprctively. In addition, there was a big difference between our research and previous research, the compound S13which was added a group at C9/C10double bond still had good activity, we imagined that the combination mode of GA and the rearrangement products were changed, and the C9/C10double bond was not necessary.5. We selected three kinds of common pathogens (Escherichia coli, Staphyloccocus aureus, Monilia albican) to evaluate the antibacterial activity of the compounds by the zone of inhibition test. The result showed that the effect on Monilia albican was better than Staphyloccocus aureus and Escherichia coli. Five of these compounds were given another MIC assay to evaluate the antibacterial activity and the MIC of the five compounds were more than125μg/ml.