Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
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DOI：
10.1021/acs.jmedchem.8b00408
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发表时间：
2018-05-10
影响因子：
7.3
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Ravindra M;Wilson MR;Tong N;O'Connor C;Karim M;Polin L;Wallace-Povirk A;White K;Kushner J;Hou Z;Matherly LH;Gangjee A
合成了新的含氟2-氨基-4-氧代-6-取代吡咯并[2，3-d]嘧啶类似物7-12，并测试了它们对叶酸受体α和β或质子偶联叶酸转运体的选择性摄取和抗肿瘤作用。化合物8、9、11和12在体外对表达FRS或PCFT的工程化中国仓鼠卵巢和HeLa细胞显示出比非氟类似物2、3、5和6高11倍的抗增殖活性。化合物8、9、11和12也抑制卵巢癌细胞的增殖；在FRα基因敲除的细胞中，化合物9、11和12表现出与PCFT摄取相关的持续抑制。所有化合物都抑制甘氨酰胺核糖核苷酸甲酰转移酶，这是从头合成嘌呤生物合成途径中的一个关键酶。分子建模研究在体外验证了基于细胞的结果。核磁共振证据支持分子内氟−氢键的存在。IGROV1异种移植在严重免疫缺陷小鼠中建立了有效的体内疗效。
Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (~11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRα, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine−hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice.
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影响因子：
50.5
作者：
Giovannetti, E.;Zucali, P. A.;Peters, G. J.
通讯作者：
Peters, G. J.
影响因子：
7.3
作者：
Gillis, Eric P.;Eastman, Kyle J.;Meanwell, Nicholas A.
通讯作者：
Meanwell, Nicholas A.
影响因子：
3.6
作者：
Desmoulin, Sita Kugel;Wang, Lei;Matherly, Larry H.
通讯作者：
Matherly, Larry H.
肿瘤以新型的6个取代的吡罗洛[2,3-d]嘧啶氨酸抗性酸酯抗凝聚酸盐，通过叶酸受体α和质子偶联的叶酸转运蛋白和protoin purine purine核苷酸生物合成的细胞摄取和杂原桥取代。
影响因子：
7.3
作者：
Golani, Lalit K.;Wallace-Povirk, Adrianne;Deis, Siobhan M.;Wong, Jennifer;Ke, Jiyuan;Gu, Xin;Raghavan, Sudhir;Wilson, Mike R.;Li, Xinxin;Poling, Lisa;de Waal, Parker W.;White, Kathryn;KushnerP, Juiwanna;O'Connor, Carrie;Hou, Zhanjun;Xu, H. Eric;Melcher, Karsten;Dann, Charles E., III;Matherly, Larry H.;Gangjee, Aleem
通讯作者：
Gangjee, Aleem
影响因子：
3.3
作者：
Chaudhari, Sachin Rama;Mogurampelly, Santosh;Suryaprakash, N.
通讯作者：
Suryaprakash, N.