Study On Drugs Of Anti-cancer Stem Cell-Design And Synthesis Of MTOR Inhibitors

Cancer stem cells play an important role in the process ofthe tumor initiation,growth,proliferation,differentiation,and apoptosis.Traditional cancer treatment methods cannot completely eradicate thisvery few but fecundous stem cells,instead they continue to induce tumorsto differentiate and leading to tumor metastasisand recurrence.Since the theory of tumor stem cells has been put forward so far,based on the development of tumor stem cells as the target of drug development that has gradually become a hot research field of anti-tumor.Mammalian rapamycin target protein(mTOR)is a protein that plays an important role in the growth of tumor stem cells.m TOR signaling pathway is one of the most easily activated pathways in tumor pathogenesis.More and more drug research and development take the mTOR signal pathway into consideration as target to inhibit or eliminate tumor stem cells,so as to achieve the purpose of cancer treatment.This paper mainly includes the following research contents:(1)Based on the study of anti-tumor of mTOR signaling pathway,and combined with the reported mTOR single crystal complex structure,two kinds of mTOR inhibitors with different structures were designed and screened by computer aided drug design software.(2)2,4,6-tribromoilide was used as raw material to synthesize benzothiazole compounds that contain 7-stepsreactionsby thiophosgene,cyclization,Buchwald-Hartwig cross-coupling reaction and Suzuki coupling,etc.All the nine target compounds wereconfirmed by ~1HNMR,MS.17 purine compounds were synthesized by Buchwald-Hartwig cross-coupling reaction,photodegradation reaction and Suzuki coupling that contained 6-step reactions with 2,6-dichloropurine as the starting materials.All the seventeen target compounds were confirmed by ~1HNMR,MS.(3)The preliminary bioactivity of selected sixteen target compounds was evaluated.The results showed that the five compounds had reached the nM level and showed good mTOR enzyme inhibitory activity.Based on this result,thestructure-activitrelationship of the compounds was summarized.