The Study Of Novel Antitumor Drugs And Corresponding Diagnostic Fluorescence Probe

Angiogenesis inhibitors have been proved effective for antitumor in clinic, while some inhibitors may exhibit resistance. Hence, multi-target agents with rational combination of cytotoxic agents and angiogenesis inhibitor have potential application. Meanwhile, the early diagnosis of tumor is very important for tumor therapy. This dissertation included two parts:1) With the study of mechanism of action of acenaphtho[1,2b]pyrrole and the evaluation of antitumor activity, a new series of multitargeted antitumor agents were designed and synthesized;2) The fluorescence probes of NAT2related with drug metabolism and disease were obtained for tumor diagnosis and personalized therapy.1. Research of antitumor mechanism of acenaphtho[1,2b]pyrrole derivatives:Our previous work reported the derivatives as FGFR1inhibitors, exhibiting good antitumor activity. We chose compound C11as representative compound for research of mechanism and further evaluation. The IC50of C11to FGFR1was19nM, and showed good selectivity to other tyrosine kinase. Also, C11could inhibit the phosphorylation of FGFR1and its downstream pathways in cells. C11effectively inhibited the proliferation of cancer cells from various tissues of human. Meanwhile, C11was able to inhibit the migration of breast cancer cells and endothelial cells. This compound exhibited good inhibition of angiogenesis.2. Novel multitargeted antitumor agents:By introducing the polyamines and alkyl chains, a new series of naphthalimide skeleton analogs were designed and synthesized. Bioassay results showed that they could inhibit the activity of topoisomerase Ⅱ and tyrosine kinases. The solubility experiments and logP showed6d-12d possessing better balance between solubility and penetration. CD spectra and fluorescence study showed that compounds with short alkyl chains exhibited good DNA intercalation, while the long ones exhibited weak interaction. kDNA experiments verified this series of compounds with good TopoⅡ inhibition. The compounds displayed good antiproliferative activity to cancer cells, and exhibited good selection to normal cells. Tyrosine kinase experiment indicated8d and12d could inhibit KDR, FGFR1and PDGFRa. It is the first time to find that this skeleton could target tyrosine kinase, which will provide a new idea for the stydy of this series of skeleton.8d was selected for further evaluation, could inhibit migration and tube formation of endothelial cells.3. The novel near-infrared fluorescence probe of N-acetyltransferase2(NAT2):Cyanine dye was chosen as fluorophore, and arylamines substrates as PET donors for the design of probes of NATs. Probe CYP1exhibited high sensitivity and selectivity to NAT2. The fluorescence intensity increased six times when NAT2added after10min. The fluorescence intensity showed good linear relationship with concentrations of NAT2, and the detection limit was1μg/mL. Furthermore, CYP1succeed in fluorescence imaging in living mice. The fluorescence intensity significantly increased in liver after10min, and the probe was completely excreted after24h. It exhibited very low background, and could detect NAT2in homogenate of liver. We also investigated the level of NAT2in various tissues, and the results were consistant with previous results by biological assay.