Studies On The Synthesis And Anti - Tumor Effects Of Derivanil Derivatives And The Synthesis Of Benzothiazepines And Anti - MDR Tuberculosis

Cancer is the second leading cause of death worldwide after cardiovascular disease. As an important class of antitumor drugs, multi-targeted small molecule tyrosine kinase inhibitors (TKIs) have been widely used in the clinic. Among them, several 4-anilinoquinazoline derivatives have been approved by US FDA for the treatment of different cancers, more candidates are under clinical or pre-clinical phases. However, improving the selectivity and avoiding drug resistance will continue to be the future research focus in this field, and the structure modification of these known TKIs is a more realistic strategy for new drug research and development.Vandetanib, approved by FDA in 2011, is the first TKI for the treatment of metastatic medullary thyroid cancer (MTC). And it is currently undergoing clinical Ⅰ-Ⅲ research for the treatment of other solid tumors. In this study, according to our recent designing method on the C-7 postion modification (nitrogen heterocyclic) of new quinolones, a series of novel Vandetanib derivatives were designed and synthesized by introducing an oxime group to the C-7 N-methylpiperidine moiety of Vandetanib. And the linkers between the piperidine ring and the oxygen atom were also investigated. Our primary objective was to identify some unique antitumor compounds, and lay a foundation for the further study.On the other hand, the rising incidence of tuberculosis (TB) infection especially multi-drug resistant TB (MDR-TB) as well as the association of TB and HIV/AIDS presents a global health problem. Therefore, it is imminent to find and develop new drugs which can control and treatment of TB especially MDR-TB effectively.In recently, benzothiazinones have been intensively studied for their new anti-TB mechanism. Among them, PBTZ169, a second generation of anti-TB candidate, is currently under phase I clinical research. In this study, a series of novel 8-nitro-6-(trifluoro)methyl benzothiazinones were designed and synthesized by structure modification on the C-2 piperazine ring of PBTZ169 including ring expansion or reduction, amino-yl migraion, oximation, further amination and so on. Our primary objective was to find some compounds which are worthy for further research and/or structure modification. This study will undoubtedly facilitate our further research in this area.The research of this dissertation could be divided into two chapters as follows:Firstly, twenty novel Vandetanib derivatives were designed, synthesized and evaluated for their in vitro antitumor activity. Compounds 1-2 (IC50:1.94 μM) and 1-13 (IC50:0.26 μM) against A549 and compound 1-10 (IC50:4.83 μM) against KB were found to be more active than or comparable to Vandetanib. Compound 1-13 was selected for further evaluation for its in vivo antitumor activity against A549, the results are coming soon and expected to be attractive. Some results have already been submitted to Chinese medicinal Biotechnology (Accepted, No.2016-0146).Secondly, a series of Benzothiazinones compounds were designed synthesized and evaluated for their in vitro antimycobacterial activity. Most of them exhibit potent activity for MTB including two MDR-MTB strains. Compounds Ⅱb1, Ⅱb2 and Ⅱc1 with best water-solubility were selected for further pharmacokinetic evaluation. The Cmax(5767 ng/mL) and AUC0-last(7579 ng-h/mL) of compound Ⅱc1 are 3.8 and 1.3 fold higher than PBTZ169. These results indicate that compound Ⅱc1 has good drugability. Currently, compound IIcl is under acute toxicity assay. The relevant results have applied for two Chinese patents (CN201610093216.6, CN201610094025.1).In this dissertation,90 compounds were synthesized,50 (including 34 target compounds) of which have been not reported in the literature yet. All of the new compounds were characterized by MS,1H NMR spectra, and some target compounds were further confirmed by 13C NMR, HRMS spectra.