吡瑞瑞辛2,4 -二氨基-6-(芳基甲基)-5,6,7,8-四氢喹唑啉类似物的合成及其抗寄生虫和抗肿瘤活性。
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Rosowsky A, Papoulis AT, Forsch RA, Queener SF
吡瑞瑞辛2,4 -二氨基-6-(芳基甲基)-5,6,7,8-四氢喹唑啉类似物的合成及其抗寄生虫和抗肿瘤活性。
中华医学化学杂志1999年3月25日;42(6):1007-17。
- PubMed ID
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10090784 (PubMed视图］
- 摘要
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19种先前未描述的2,4-二氨基-6-(芳基甲基)- 5,6,7,8 -四氢喹唑啉(5a-m, 10-12)被合成，作为评估亲脂性二氢叶酸还原酶(DHFR)抑制剂对艾滋病机会性感染的治疗潜力的更大努力的一部分。将适当取代的(芳基甲基)三苯磷烷与4,4 -乙烯二氧环己酮缩合，然后加氢(H2/Pd-C)和酸解反应，得到相应的4-(芳基甲基)环己酮，然后与氰胍缩合生成四氢喹唑啉。以市售的4-烷基环己酮为原料，用此方法一步制备了3种简单的2,4 -二氨基-6-烷基-5,6,7,8-四氢喹唑啉模型化合物(9a-c)。对大鼠肝脏DHFR、卡氏肺孢子虫DHFR和刚地弓形虫DHFR- ts双功能酶进行了酶抑制实验，分别测定了IC50(大鼠)/IC50(P。IC50(大鼠)/IC50(T。Gondii)进行比较。3种抑制卡氏假单胞菌DHFR活性最强的抑制剂分别为2,5-二甲氧基苄基(5j)、3,4 -二甲氧基苄基(5k)和3,4,5-三甲氧基苄基(5l)类似物，IC50值分别为0.057、0.10和0.091 microM。其余化合物的IC50值一般在0.1-1.0 microM范围内。然而，所有化合物对大鼠肝酶的抑制作用都比卡氏P. carinii酶强，因此是非选择性的。弓形虫酶总是比卡氏疟原虫酶更敏感，大多数类似物的IC50值为0.01-0.1微米。 Moderate 5-10-fold selectivity for T. gondii versus rat liver DHFR was observed with five compounds, the best combination of potency and selectivity being achieved with the 2-methoxybenzyl analogue 5d, which had an IC50 of 0.014 microM and a selectivity ratio of 8.6. One compound (5l) was tested for antiproliferative activity against P. carinii trophozoites in culture at a concentration of 10 microgram/mL and was found to completely suppress growth over 7 days. The suppressive effect of 5l was the same as that of trimethoprim (10 microgram/mL) + sulfamethoxazole (250 microgram/mL), a standard clinical combination for the treatment of P. carinii pneumonia in AIDS patients. Four compounds (5a,h,k,l) were tested against T. gondii tachyzoites in culture and were found to have a potency (IC50 = 0.1-0.5 microM) similar to that of pyrimethamine (IC50 = 0.69 microM), a standard clinical agent for the treatment of cerebral toxoplasmosis in AIDS patients. Compound 5h was also active against T. gondii infection in mice when given qdx8 by peritoneal injection at doses ranging from 62.5 (initial dose) to 25 mg/kg. Survival was prolonged to the same degree as with 25 mg/kg clindamycin, another widely used drug against toxoplasmosis. Three compounds (5j-l) were tested for antiproliferative activity against human tumor cells in culture. Among the 25 cell lines in the National Cancer Institute panel for which data were confirmed in two independent experiments, the IC50 for at least two of these compounds was <10 microM against 17 cell lines (68%) and in the 0. 1-1 microM range against 13 cell lines (52%). One compound (5j) had an IC50 of <0.01 microM against four of the cell lines. The activity profiles of 5k,l were generally similar to that of 5j except that there were no cells against which the IC50 was <0.01 microM.