The Study Of The Multigram-scale Synthesis And Mitochondrial-Targeted Prodrug Of A Anti-hepatoma Fluorinated Docetaxel

Paclitaxol and docetaxel, used as the first-line treatment of various cancer in clinic, are two of the most important anti-tumor drugs. However, the metabolic instability, multiple drug resistance, low aqueous solubility and strong side effects during treatment are major obstacles for effective cancer therapy.9fluorinated Docetaxel derivatives have been obtained in our previous study, in which fluorine atoms replaced the hydrogen atoms easily oxidized by P450enzymes in vivo. All of these compounds showed better metabolic stability than its leading compound docetaxel in the subsequent pharmacological study. Especially the compound4FDT exhibited good anti-tumor activity, metabolic stability and safety. As a result,4FDT was chosen for further study.At first,4FDT was synthesize in gram scale and tested in an extensive anti-tumor activity screen which contained13tumor cells.4FDT showed good anti-hepatoma activity in vitro and in vivo. And the safety test and aqueous solubility study showed that4FDT was a drugable candidate for anti-liver cancer.Therefore, we decided to synthesize4FDT in multi-gram scale. After two-year tough and creative work,152.4g4FDT was obtained from2000g10DAB through nine steps at total yield4.7%. The manufacturing and purifying technics of4FDT was optimized and finally determined in the process, the removal of organic solvent residual was also determined. All the synthesized4FDT was above the standard of raw drug according to the Chinese Pharmacopoeia. In addition, the quality control specification of4FDT was established under the joint efforts of us and colleagues from the Department of Analytical Chemistry.Moreover, to up-regulate the bioavailability and minimize the systematic toxicity of4FDT, a rhodamine B labeled fluorinated docetaxel (4FDT-β-Ala-RhB) was designed under optical-image-guided cancer therapy, in which4FDT and rhodamine B were conjugated via a biodegradable β-alanine bond as a chemotherapeutic reagent and as an imaging reporter and targeting domain, respectively. In vitro image studies demonstrated the morphological changes of tubulin and chromosomal alterations of human liver cancer cells HepG2, which were similar to the phenomena observed after treatment with the active drug4FDT. And pharm logical studies implied the consistent release of the active drug from the prodrug throughout the incubation period via the linear increase in the cytotoxicity observed as a function of time. Additionally, the specific delivery of the prodrug to mitochondria was observed by fluorescent microscopy. One paper related to this work was submitted to European Journal of Pharmaceutics and Biopharmaceutics.At last, based on the X-Ray crystal conformation of4FDT that was obtained in previous work, the relationship of crystal conformation and bio-active conformation was studied. Novel macro-cyclic4FDT analogues was designed and the synthetic work is being processed now. This work would provide the rational basis of active site of4FDT and the possibility to design4FDT derivatives with less complicate structure and better anti-tumor activity.Above all, on the basis of the new discovered anti-hepatoma4FDT, a lot of creative and hard work has been done from the technical research to the fundamental research. These studies had been financial supported by a number of funds, which would help to develop the novel anti-hepatoma drugs with Chinese intellectual property rights.