Jackman A L, Bisset G M, Jodrell D I, Gibson W, Kimbell R, Bavetsias V, Calvert A H, Harrap K R, Stephens T C, Smith M N
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Adv Exp Med Biol. 1993;338:579-84. doi: 10.1007/978-1-4615-2960-6_118.
Our search for water-soluble quinazoline TS inhibitors that are transported into cells via the RFC, but are not substrates for FPGS, led us to the synthesis of dipeptide analogues of ICI 198583 diglutamate. Although a number of dipeptide analogues were active against isolated TS and L1210 cells in vitro, lack of in vivo stability was a problem. This was circumvented by the synthesis of modified dipeptides where either the alpha-carboxyl of the second amino acid was removed (alpha'-COOH) e.g. -L-glu-GABA or where the second amino acid was the unnatural D-enantiomer e.g.-L-glu-D-glu. Further studies were performed with the -L-glu-D-glu and its 7-CH3, 2'F modified analogue, demonstrating that they use the RFC for cell entry but are not active through polyglutamate formation. The latter compound was tested against experimental tumour models and found to have good activity.
我们致力于寻找通过还原叶酸载体（RFC）转运进入细胞，但不是叶酸聚谷氨酸合成酶（FPGS）底物的水溶性喹唑啉胸苷酸合成酶（TS）抑制剂，这促使我们合成了ICI 198583二谷氨酸的二肽类似物。尽管许多二肽类似物在体外对分离的TS和L1210细胞具有活性，但缺乏体内稳定性仍是一个问题。通过合成修饰的二肽来规避这一问题，其中第二种氨基酸的α-羧基被去除（α'-COOH），例如-L-谷氨酸-γ-氨基丁酸，或者第二种氨基酸是天然的D-对映体，例如-L-谷氨酸-D-谷氨酸。对-L-谷氨酸-D-谷氨酸及其7-CH3、2'F修饰的类似物进行了进一步研究，结果表明它们通过RFC进入细胞，但不会通过形成聚谷氨酸而具有活性。对后一种化合物进行了实验性肿瘤模型测试，发现其具有良好的活性。
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