新型含氟嘌呤喹唑啉酮类PI3Kδ抑制剂的设计合成与活性研究

Design,Synthesis,and Activity of Novel Fluorine-Containing Purine Quinazolinones as PI3KδInhibitors

基于PI3Kδ抑制剂IC-87114的结构和氟原子的特点,以2-氨基-6-甲基苯甲酸为起始原料,设计并合成了3个新型含氟嘌呤喹唑啉酮类PI3Kδ抑制剂Ⅲa、Ⅲb、Ⅲc,通过^(1)HNMR、LC-MS等对其结构进行了表征,并对其抗肿瘤活性进行了评价。结果表明,氟原子取代位置不同的PI3Kδ抑制剂的抗肿瘤活性不同,但均能明显抑制结肠癌小鼠肿瘤生长,且Ⅲa的抑制效果整体较IC-87114原药的更为明显。

On the basis of the structure of PI3Kδinhibitor IC-87114 and fluorine atom characteristics,we synthesized three novel fluorine-containing purine quinazolinones as PI3KδinhibitorsⅢa,Ⅲb,Ⅲc by using 2-amino-6-methylbenzoic acid as a starting material.Moreover,we characterized their structures by ^(1)HNMR and LC-MS,and evaluated their antitumor activities.The results show that the antitumor activities of PI3Kδinhibitors with fluorine substituents at different positions are different,but they can significantly inhibit the tumor growth of colorectal cancer mice,and the inhibitory effect ofⅢa is superior to that of original drug IC-87114.