二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮的合成及生物活性研究

Synthesis and Biological Activities of Dihydrooxazolo[5,4-d]-pyrrolo[1,2-a]pyrimidinones

以天然产物脱氧鸭嘴花酮生物碱为基础,通过生物电子等排手段,设计并合成了40个二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶酮类化合物,其结构经^(1)HNMR、^(13)CNMR和HRMS进行了确证,并对该类化合物合成方法的关键步骤影响因素和构效关系进行了探讨.使用噻唑蓝(MTT)法对该系列化合物的3种肿瘤细胞(MCF-7、Hela、A549)的体外抗肿瘤活性进行了研究,采用琼脂打孔法对该系列化合物的抑菌活性也进行了初步评价.结果表明,2-(萘-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E12)和2-(4-(三氟甲氧基)苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E39)对He La和MCF-7有较强的抗肿瘤增殖活性,半抑制浓度(IC_(50))值分别为(4.59±0.10)和(6.89±1.26)μmol·L^(-1);2-((3R,5R,7R)-金刚烷基-1-基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E6)和2-(3,5-二氯苯基)-6,7-二氢噁唑并[5,4-d]吡咯并[1,2-a]嘧啶-9(5H)-酮(E28)对白色念珠菌(C.albicans)、大肠杆菌(E.coli)和金黄色葡萄球菌(S.aureus)有较好的抑菌活性.

Based on the general framework of natural alkaloid deoxyvasicinone,forty dihydrooxazolo[5,4-d]pyrrolo[1,2-a]-pyrimidinone compounds were designed and synthesized through bioisosterism strategy.The novel compounds were confirmed by^(1)H NMR,^(13)C NMR and HRMS spectra.The main factors affecting the reactions of synthesis and the structure-activity relationships(SARs)were investigated.The activities of the target compounds against three cancer cell lines(MCF-7,He La and A549)were evaluated by methyl thiazolyl tetrazolium(MTT)in vitro.All the compounds were also evaluated for their antimicrobial activities by agar punch method.The results showed that 2-(naphthalen-1-yl)-6,7-dihydrooxazolo[5,4-d]-pyrrolo[1,2-a]pyrimidin-9(5H)-one(E12)and 2-(4-(trifluoromethoxy)phenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one(E39)exhibited relatively better anti-proliferative activities against He La and MCF-7 cancer cell lines,with the half maximal inhibitory concentration(IC_(50))values of(4.59±0.10),(6.89±1.26)μmol·L^(-1),respectively.2-((3R,5 R,7R)-Adamantan-1-yl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one(E6)and 2-(3,5-dichlorophenyl)-6,7-dihydrooxazolo[5,4-d]pyrrolo[1,2-a]pyrimidin-9(5H)-one(E28)showed good antimicrobial activity to C.albicans,E.coli and S.aureus.