Design,Synthesis And Anticancer Activities Of Novel Thiazolopyrimidinones

Quinazolinone and its analogues exhibit excellent drug-like properties and extensive biological activities.Therefore,they have received considerable attention in drug discovery.Luotonin A is a quinazolinone alkaloid with antitumor activity.In this paper,a series of thiazolo[4,5-d]pyrimidin-7（6H）-ones were rationally designed and synthesized based on bioisosterism strategy.We gradually explored the target compounds synthetic route,antitumor activity in vitro and in vivo.The specific contents are as follows:1.A new class of thiazopyrimidinones as anticancer drugs were designed and synthesized.A series of novel 2-amino-5-arylthiazol pyrimidinone derivatives were designed.The synthesis route was developed,which were composed of Thorpe-Ziegler reaction,I₂/DMSO-mediated thiazopyrimidine ketone synthesis,thioether oxidation and nucleophilic substitution reaction.A total of22 unreported target compounds which contain thiazolopyrimidinone skeleton were synthesized.The synthesis method has the advantages of cheap and easily available raw materials,simple operation,and high yield.2.The evaluation of in vitro and in vivo antitumor activities and toxicity of target compounds.MTT assay was performed to detect the inhibitory effect of the target compounds on the proliferation of A549,HepG2 and MCF-7 cell lines in vitro.The results showed that most of targeted compounds exhibited potent anti-tumor activities.Compounds 4h（LW-1）,4g,4i,4n,4p,and 4t showed the highest activities.Among them,LW-1 inhibited the growth of A549,HepG2,and MCF-7 cell lines with IC₅₀0 value of 3.4μM,3.4μM,and 2.8μM,respectively.The structure-activity relationships were summarized as follows:（1）The piperazine group at the 2-position was necessary for the activity.（2）The 3,5-dichlorobenzene group at the 5-position was preferred for the activity.（3）The bulk size of the 6-substituent was positively correlated with the anti-tumor activity.In vivo study showed that LW-1 could significantly inhibited the growth of implanted H22 hepatoma in mice.Treatment with LW-1 at doses of 25 and50 mg/Kg daily resulted in tumor inhibitory rates of 35.66%and 60.34%,respectively.And LW-1 was found to be orally safe.There was no obvious acute toxicity when the single dose of 1000 mg/Kg was given intragastrically.