Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents
Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents
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DOI：
10.1021/jm991119p
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发表时间：
2000-05-18
影响因子：
7.3
通讯作者：
Jackman, AL
中科院分区：
文献类型：
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作者：
Bavetsias, V;Marriott, JH;Jackman, AL
随着雷替曲塞的开发，不使用还原叶酸载体（RFC）进入细胞的非多聚谷氨酸TS抑制剂的合成应提供克服对基于叶酸的TS抑制剂耐药机制的化合物，这些耐药机制与叶酸多聚谷氨酸合成酶（FPGS）表达降低/改变和/或RFC受损相关。检查的计算机图形模型的人源化大肠杆菌TS酶与喹唑啉抑制剂的TS，如1结合在酶的活性位点，表明通过桥接C9与C7形成一个五肽的构象限制可能是有益的结合到TS。这导致了一系列基于环戊[g]喹唑啉的酶的有效抑制剂的合成，其中与经典抗叶酸剂相关的谷氨酰残基被各种谷氨酸衍生的配体取代;最有效的抑制剂是L-Glu-γ-D-GluT（alpha）衍生物7 j。在小鼠L1210：1565细胞系（突变RFC）中，大多数这些化合物的活性与亲本L1210细胞系相等或仅略高，表明L1210细胞系中细胞摄取对RFC的依赖性降低。
Following the development of raltitrexed, the synthesis of nonpolyglutamatable inhibitors of TS that do not use the reduced folate carrier (RFC) for cellular entry should provide compounds which overcome mechanisms of resistance to folate-based inhibitors of TS that are associated with decreased/altered folylpolyglutamate synthetase (FPGS) expression and/or an impaired RFC. Examination of a computer graphics model of the humanized Escherichia coli TS enzyme with quinazoline inhibitors of TS, such as 1 bound in the active site of the enzyme, suggested that conformational restriction introduced by bridging the C9 with C7 to form a pentacycle may be beneficial for binding to TS. That led to the synthesis of a series of potent cyclopenta[g]quinazoline-based inhibitors of the enzyme in which the glutamyl residue associated with classical antifolates was replaced with a variety of glutamate-derived ligands; the most potent inhibitor being the L-Glu-gamma-D-GluT(alpha) derivative 7j. In the mouse L1210:1565 cell line (mutant RFC), the majority of these compounds had activity equal or only slightly greater compared with the parental L1210 cell line, indicating a reduced dependence on the RFC for cellular uptake in the L1210 cell line.