Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions 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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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。
DOI：
10.1021/acs.jmedchem.6b00594
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发表时间：
2016-09-08
影响因子：
7.3
通讯作者：
Gangjee, Aleem
中科院分区：
文献类型：
--
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
合成了靶向抗叶酸剂，其中1中苯环附近的碳原子被N（4）、O（8）或S（9）杂原子取代，或被N-取代的甲酰基（5）、乙酰基（6）或三氟乙酰基（7）部分取代，并测试了叶酸受体（FR）α和β或质子偶联叶酸转运蛋白的选择性细胞摄取。结果显示，相对于CH 2类似物1，对表达FR的工程化中国仓鼠卵巢细胞的体外抗增殖活性增加4-9。化合物4-9抑制从头嘌呤生物合成和甘氨酰胺核糖核苷酸甲酰转移酶（GARFT酶）。4与FRα和GARFT酶的X射线晶体结构表明，4的结合构象需要柔性才能与FRα和GARFT酶结合。在携带IGROV 1卵巢肿瘤异种移植物的小鼠中，4是高度有效的。我们的研究结果表明，杂原子取代的3-原子桥区域的6-取代的吡咯并[2，3-d]嘧啶相关的1提供了有针对性的抗叶酸剂，值得进一步评估作为抗癌剂。
Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro anti-proliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4–9 over the CH2 analog 1. Compounds 4–9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.6
作者：
Desmoulin, Sita Kugel;Wang, Lei;Matherly, Larry H.
通讯作者：
Matherly, Larry H.
影响因子：
8.8
作者：
Bissett D;McLeod HL;Sheedy B;Collier M;Pithavala Y;Paradiso L;Pitsiladis M;Cassidy J
通讯作者：
Cassidy J
影响因子：
3.4
作者：
Boritzki, TJ;Barlett, CA;Jackson, RC
通讯作者：
Jackson, RC
影响因子：
3
作者：
Budman, DR;Johnson, R;Walling, J
通讯作者：
Walling, J