Design, Synthesis And Antitumor Activities Of Tumor Vascular-targeted Drugs

Malignant tumors represent one of the most common diseases of globel,andimpact on human’s health and quality of life seriously. In recent years, due to the thebad habits and deterioration of living environment, tumor cases increased year by year.So a reasonable means of cancer treatment is particularly important.The blood vessels of tumors can provide all metabolic substance as the tumorsgrowing. So targeting tumor blood vessels becomes an effective means to thecancer treatment. Comparing with conventional anticancer drugs, targeting tumorvascular therapy has many advantages of high efficiency, low toxicity andbroad-spectrum. Tumor vascular-targeted drugs can directly act on tumor vascularendothelial cells, and treat effectively for the most types of tumors which depend onthe vascular system.Today, targeting tumor vascular therapy as a new treatment isbeing constantly applied to the clinical.Tumor vascular-targeted agents are a class of new cancer therapenticdrugs,which include vascular disrupting agents and antiangiogenic agents, and havemade significant research progress in recent years. As the classic vascular disruptingagents,tubulin binding agents have been to attract broad attention with the features ofsmall cytotoxic, fast-acting. Antiangiogenic agents target directly to the vascularendothelial cells and interfere with the newborn process of tumor blood.Theirtargeting spots include blocking angiogenic factors (such as VEGF, bFGF).Antiangiogenic agents are only effective for tumor angiogenesis,and apply in theprevention and treatment of early stage or systemic metastasis of solid tumors.Theyhave small side effects and less drug resistance, but have the poor efficacy to thegenerated tumor vasculature.There are differences in the therapentic mechanism, timing of treatment andtreatment characteristics between vascular disrupting agents and antiangiogenicagents,and combination therapy of them is beneficial to clinicaltreatment.Therefore,it has been to attract broad attention for the reaserch anddevelopment of the dual inhibitors of vascular disrupting and angiogenesis recently.This thesis is dedicated to the study of two aspects: First,design and synthesis ofnovel4-phenyl pyrimidine compounds with the lead compound of dual inhibitorIMC-03852;Second, design of different3-substituted indole-2-one compounds withthe receptor tyrosine kinase inhibitor SU5416as the lead compounds.1. Design, Synthesis, and antitumor activities in vitro of novel4- Design of a class of4-phenyl pyrimidine compounds according to thestructure-activity relationship and the principle of molecular folded and the skeletontransition of IMC-038525,the lead compound of tumor vascular-targeted dual inhibitor.Design the synthetic route of target compounds based on structural analysis andliterature research of it. Phenylboronic acid and2,6-dichloropyrimidine as startingmaterials, synthesis the target compounds through six-step reaction of nitration,reduction, condensation and coupling. All25target compounds were synthesized andreported firstly and their chemical structures were confirmed by1HMNR and MS.Investigated the in vitro antitumor activity of all target compounds, some of thecompounds of tubulin inhibitory activity and VEGFR2kinase inhibitory activity. Theresults showed that all the target compounds had anti-tumor activity in vitro. Theinhibition rate on eight test tumors of compounds A15, A23and A25was similar todocetaxel; the compounds A15and A23had a certain degree of tubulinpolymerization inhibitory activity, the compounds A15and A25of the VEGFR2kinase inhibitory activity; mostly compound A15inhibited tubulin polymerization andVEGFR2kinase activity, showing that the initial dual inhibitory activity of vasculardisrupting and angiogenesis.2. Design, Synthesis, and antitumor activities in vitro of novel3-substitutedindolin-2-one compoundsTyrosine receptor kinase inhibitor SU5416as a lead compound, combined withthe CA4structure-activity relationship and pharmacophore features, we designed ofdifferent substituted3-substituted indole-2-one compounds. Substituted aniline as thestarting material, synthesized the target compounds by five-step reaction withcondensation, cyclization and reduction. All41target compounds were synthesizedand reported firstly and their chemical structures were confirmed by1HMNR and MS.Optimized of the reduction reaction of indole ketone as key intermediate.Triethylsilane/trifluoroacetic acid were used as a reducing agent instead of hydrazinehydrate in literature. The new reduction method had several advantages such as higheryield(above89%)、 simple work-up procedure, mild reaction conditions(roomtemperature). Cultured of single crystals of some target compounds compounds anddetermined of the target compounds Z/E isomers by single crystal X-ray diffraction.Summarized the law of1HNMR’s chemical shifts of the characteristic ene hydrogenand2’/6’ hydrogen of the Z/E isomers. inhibitory activity and VEGFR2kinase inhibitory activity. The results showed that:the benzene ring of the indole ketone of5-OH-6-OMe replaced, inhibition IC50ofcompound B6and B9on three cell strains up to10~80μM; and replaced by4,5,6-OMe, Z configuration compounds’antitumor activity are generally better than the Econfiguration. Inhibition IC50of compound B16, B17, B22and B23on three cellstrains reach to5~90μM. In addition, the compound B9had a certain degree of theinhibitory activity of tubulin and VEGFR-2kinase in vitro.The work was supported by National Natural Science Foundation (No.21172260)and Shanghai basic research key topics (No.09JC1417500).