Synthesis And Antitumor Activity Evaluation Of Taxane And Phloretin Derivetives

Cancer is the second most common cause of death in the human after heartdisease. According to World Health Organization statistics, there are around800million people died of cancer in2007, accounting for14%of the total annualnumber of deaths. It is estimated that in2015there would be900million peopledied of cancer, and in2030this figure would reach to11.4million. Cancer hasposed a great threat to human survival, therefore, there is an urgent need todevelop new anti-cancer drugs with high efficacy, low toxicity.In the research and development of many new anticancer drugs, anticancerdrugs derived from natural products are concerned. According to statistics, in thepast25years,63%of the anti-cancer drugs directly or indirectly derived fromnatural products. As a diterpene skeleton of taxanes, taxol is extracted from thebark of the Pacific yew (Taxus, brevifolia) in the sixties of the last century. Thisis considered to be one of the important achievements of the20th century in anti-cancer drugs field due its unique mechanism and anticancer effect.Since December1992, the FDA approved taxol for the treatment ofadvanced ovarian cancer, its application in the clinical gradually expanded, now taxol has been used to treat breast cancer, lung cancer, esophageal cancer, gastriccancer, metastasis and recurrent ovarian cancer and so on. However, taxol, anatural tetracyclic diterpenoid substances, with very complicated structure, haspoorly water solubility and low bioavailability, which restrict its clinicalapplication. Docetaxel, a second generation taxane anticancer drug, whichactivity is2-3times that of paclitaxel and its action mechanism is same to taxol,has better bioavailability, less toxicity, and broader scope.Phloretin, a naturally occurring flavonoid, belongs to the chemical class ofdihydrochalcones, and it consists of a C6–C3–C6skeleton structure (twoaromatic rings connected by a C3chain). Phloretin is mainly present in apples,pears, and other juicy fruits. It has shown various biological activities such asantioxidative, anti-inflammatory and antimutagenic effects. Recently, itsantitumor property has also attracted much attention to pharmaceutists. Manystudies indicate that phloretin could inhibit proliferation of some tumor cells andinduce their apoptosis. Phloretin has broad antitumor spectrum.Phloretin and its derivatives have a broad and important role in variousfields of human health and have become one of the hot spots of the naturalproducts research. Numerous studies show that phloretin has anticancer effects,but the research on antitumor activities of phloretin derivatives is almost blank.In the light of the structure-activity relationships of taxol and docetaxel andthe experimental facts of phenylisoxazole or phenyloxadiazole compounds withanticancer activity, we designed three types of60new taxane compounds, whichintroduced substituted phenyl isoxazole or substituted phenyl oxadiazol in thean amide group of C-3’ in C-13side chain. We used computer to virtually screena constructed taxane small molecule library in view of pharmacophore byutilizing Disscovery Studio3.1software and screenned out12novel taxaneswith better antitumor activity.According to research condition of taxol and phloretin at home and broad, we synthesized7C-13side chain compounds,29C-13side chain intermediates,1taxane,2taxane intermediates and9phloretin derivatives, which have notbeen reported. We also got single crystal X-diffraction data of17newcompounds never reported. The structures of all new compounds werecharacterized and antitumor activity of some compounds were evaluated. Thedetailed contents are as follows:1. Designed and synthesized for the first time6C-13side chaincompounds and20new C-13side chain intermediates that hadoxadiazole skeleton. Their structures were characterized by NMR andMS.7single crystals were obtained and their structures weredetermined by X-ray single crystal diffraction. Antitumor activity of12compounds were evaluated.2. Designed and synthesized for the first time1C13-side chain compoundand10new C13-side chain intermediates that had isoxazole skeleton.Their structures were characterized by NMR and MS. Antitumoractivity of4compounds were evaluated.3. Designed and synthesized for the first time1taxane which C-3’hasoxadiazole skeleton and2novel taxane intermediates. Their structureswere characterized by NMR and MS.4. The nine novel phloretin derivatives were designed and synthesized forthe first time, the structures of the compounds were characterized byNMR and MS.10single crystals were obtained and their structureswere determined by X-ray single crystal diffraction. Antitumor activityof9phloretin derivatives, phloretin, phlorizin, resveratrol andacetylated resveratrol were evaluated. The results showed thatcompounds46b、46c and51inhibited the proliferation of SPC-A1,EC109, A549, MDA-MB-231and MCF-7cell lines, which wasobviously better than docetaxel. The antitumor activity of other compounds was barely better, weaker than docetaxel.This article would provide an experimental data and theoretical basis forthe design and synthesis of novel taxanes, as well as for phloretin derivatives inthe research and the development of anticancer drugs.