6-取代吡咯并[2,3-d]嘧啶噻吩甲酰基区域异构体的合成及生物活性作为从头嘌呤生物合成的抑制剂，对高亲和力叶酸受体和质子偶联叶酸转运体的细胞摄取具有选择性，而对还原叶酸载体的摄取则较低。
Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier.
机构信息
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
出版信息
J Med Chem. 2012 Feb 23;55(4):1758-70. doi: 10.1021/jm201688n. Epub 2012 Feb 3.
Abstract
We previously reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and l-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC.
摘要
我们之前报道了具有噻吩甲酰基取代苯甲酰基侧链和三（3a）和四碳（3b）桥的经典 2-氨基-4-氧代-6-取代吡咯并[2,3-d]嘧啶的选择性转运。化合物 3a 对肿瘤细胞的活性比 3b 更强。虽然 3b 对叶酸受体 (FRs) 和质子偶联叶酸转运蛋白 (PCFT) 的转运具有完全选择性，而对还原叶酸载体 (RFC) 则没有，但 3a 并非如此。为了确定减少 3b 中环丙二酰基支架和 l-谷氨酸之间的距离是否会保留对人类肿瘤细胞的转运选择性和效力，我们合成并评估了噻吩甲酰环上具有 [1,3]（7 和 8）和 [1,2]（4、5 和 6）取代以及在四原子桥中具有炔插入的 3b 区域异构体。化合物 7 和 8 对 KB 和 IGROV1 人类肿瘤细胞具有强效的纳摩尔抑制作用，对 FRα 和 PCFT 具有完全选择性，而对 RFC 则没有。
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