Synthesis and antifolate evaluation of the 10-propargyl derivatives of 5-deazafolic acid, 5-deazaaminopterin, and 5-methyl-5-deazaaminopterin.
Synthesis and antifolate evaluation of the 10-propargyl derivatives of 5-deazafolic acid, 5-deazaaminopterin, and 5-methyl-5-deazaaminopterin.
复制标题
5-脱氮叶酸、5-脱氮氨基蝶呤和5-甲基-5-脱氮氨基蝶呤的10-炔丙基衍生物的合成和抗叶酸评价。
DOI：
10.1021/jm00080a019
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发表时间：
1992
影响因子：
7.3
通讯作者：
Sirotnak,FM
中科院分区：
文献类型：
--
作者：
Piper,JR;Malik,ND;Rhee,MS;Galivan,J;Sirotnak,FM
5-Deaza-10-propargylfolic arid (4) 是胸苷酸合成酶 (TS) 抑制剂 10-propargyl-5, 8-dideazafolic arid (PDDF, 1) 的类似物，通过 2-amino-6-(bromomethyl)-4 对 JV-[4-(propargylamino) 苯甲酰基]-L-谷氨酸二乙酯 (7) 进行烷基化来制备(3fl)-吡啶并[2, 3-d]嘧啶酮(15)。溴甲基中间体15由相应的羟甲基前体14通过用48％HBr处理来制备。通过在回流的1N NaOH中使报道的2, 4-二氨基吡啶并[2, 3-d]嘧啶-6-甲醇(12a)脱氨基获得羟甲基化合物14。 12a 及其 5-甲基取代的类似物 12b 均被转化为通用的 6-溴甲基中间体 13a 和 13b，从中可以容易地衍生出重要的抗叶酸剂。 7被13a、b烷基化得到10-炔丙基-5-脱氮氨基蝶呤(5)和5-甲基-10-炔丙基-5-脱氮氨基蝶呤(6)。作为 H35F/F 细胞的 TS 抑制剂，4 的 ICgg 值表明其抑制作用比 PDDF 低约 6 倍（4 为 90 nM，PDDF 为 14 nM）。在体外研究中，4 vs L1210 和 S180 获得的 IC50 (μ) 值分别为 1.50 和 2.35，与 PDDF 获得的值相似（2.61 和 1.97）。针对 HL60 细胞，4 的细胞毒性比 PDDF 高约 7 倍（IC50 值分别为 0.72 和 5.29 µ）。包含胸苷并没有将 TS 确定为所用细胞系中 4 或 PDDF 的细胞毒性作用位点。在针对L1210的小鼠体内试验中，4种未能显示出治疗效果。 2, 4-二氨基化合物5和6是L1210细胞DHFR的有效抑制剂，分别是MTX和7倍和35倍，对L1210细胞生长的抑制作用比MTX更强。在介导的 L1210 细胞流入中，5 和 6 的转运分别是 MTX 的 2.7 倍和 8.5 倍，比 MTX 更容易。对小鼠E0771乳腺癌，6比MTX产生更强的抗肿瘤作用。每天36毫克/公斤的剂量，持续5天，没有引起中毒性死亡，同时10只小鼠的平均肿瘤体积减少到对照组的8-9%，并且20%的试验动物没有肿瘤。
5-Deaza-10-propargylfolic arid (4), an analogue of the thymidylate synthase (TS) inhibitor 10-propargyl-5, 8-dideazafolic arid (PDDF, 1), was prepared via alkylationof diethyl JV-[4-(propargylamino) benzoyl]-L-glutamate (7) by 2-amino-6-(bromomethyl)-4 (3fl)-pyrido [2, 3-d] pyrimidinone (15). Bromomethyl intermediate 15 was prepared from the corresponding hydroxymethyl precursor 14 by treatment with 48% HBr. Hydroxymethyl compound 14 was obtained by deamination of reported 2, 4-diaminopyrido [2, 3-d] pyrimidine-6-methanol (12a) in refluxing 1N NaOH. Both 12a and its 5-methyl-substituted analogue12b were converted to versatile 6-bromomethyl intermediates 13a and 13b from whichimportant antifolates may be readily derived. Alkylation of 7 by 13a, b led to 10-propargyl-5-deazaaminopterin (5) and5-methyl-10-propargyl-5-deazaaminopterin (6). As an inhibitor of TS fromH35F/F cells, 4 gave an ICgg value showing it to be approximately 6-fold less inhibitory than PDDF (90 nM for 4 vs 14 nM for PDDF). In in vitro studies, IC50 (µ) values obtained for 4 vs L1210 and S180 of 1.50 and 2.35, respectively, were similar to those obtained for PDDF (2.61 and 1.97). Against HL60 cells, 4 was about 7-fold more cytotoxic than PDDF (IC50 values 0.72 and 5.29 µ). Inclusion of thymidine did not establish TS as the site of cytotoxic action for either 4 or PDDF in the celllines used. In in vivo tests against L1210 in mice, 4 failed to show therapeutic effect. The 2, 4-diamino compounds 5 and 6 were as potent inhibitors of DHFR from L1210cells as MTX and 7-and 35-fold, respectively, more inhibitory than MTX towardL1210 cell growth. In mediated influx into L1210 cells, 5 and 6 were transported 2.7-and 8.5-fold, respectively, more readily than MTX. Against the E0771 mammary adenocarcinoma in mice, 6 produced greater antitumor effect than MTX. A dose of 36 mg/kg per day for 5 days caused no toxic deaths while the average tumor volume among 10 mice was reduced to 8-9% of that of the control, and 20% of the test animals were rendered tumor free.