DeGraw J I, Colwell W T, Piper J R, Sirotnak F M
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025.
J Med Chem. 1993 Jul 23;36(15):2228-31. doi: 10.1021/jm00067a020.
Successive alkylation of dimethyl homoterephthalate with propargyl bromide and 2,4-diamino-6-(bromomethyl)pteridine followed by ester saponification at room temperature afforded 2,4-diamino-4-deoxy-10-carboxy-10-propargyl-10-deazapteroic acid. The 10-COOH was readily decarboxylated by heating in DMSO at a temperature of only 120 degrees C to yield the diamino-10-propargyl-10-deazapteroic acid intermediate. Coupling with diethyl L-glutamate and ester hydrolysis gave the title compound. The 10-propargyl analogue was about 5 times more potent than MTX as an inhibitor of growth in L1210 cells, but was only one-third as potent as an inhibitor of DHFR from L1210. The analogue was transported inward very effectively in L1210 cells showing a 10-fold advantage over MTX. At a dose of 36 mg/kg the 10-propargyl compound caused shrinkage of the E0771 solid murine mammary tumor to only 1% of untreated controls.
对苯二甲酸二甲酯与炔丙基溴和2,4-二氨基-6-(溴甲基)蝶啶进行连续烷基化反应，然后在室温下进行酯皂化反应，得到2,4-二氨基-4-脱氧-10-羧基-10-炔丙基-10-脱氮蝶酸。通过在仅120℃的温度下于二甲基亚砜中加热，10-COOH很容易脱羧，生成二氨基-10-炔丙基-10-脱氮蝶酸中间体。与L-谷氨酸二乙酯偶联并进行酯水解得到标题化合物。作为L1210细胞生长抑制剂，10-炔丙基类似物的效力约为甲氨蝶呤（MTX）的5倍，但作为L1210二氢叶酸还原酶（DHFR）抑制剂的效力仅为MTX的三分之一。该类似物在L1210细胞中非常有效地向内转运，显示出比MTX高10倍的优势。在剂量为36 mg/kg时，10-炔丙基化合物使E0771小鼠实体乳腺肿瘤缩小至未治疗对照组的仅1%。
