Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis
文献类型：期刊论文
| 作者 | Golani, Lalit K.2; Wallace-Povirk, Adrianne3; Deis, Siobhan M.5; Wong, Jennifer5; Ke, Jiyuan6,7; Gu, Xin6,7; Raghavan, Sudhir2; Wilson, Mike R.4; Li, Xinxin2; Poling, Lisa3,4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-09-08 |
| 卷号 | 59期号:17页码:7856-7876 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6b00594 |
| 文献子类 | Article |
| 英文摘要 | 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 form-yl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (PR) alpha and beta or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinarnide ribonudeOtide formyltransferase (GARFTase). X-ray crystal structures for 4 with FR alpha and GARFTase showed that the bound conformations Of 4 required flexibility for attachment to both FR alpha 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. |
| WOS关键词 | GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE ; CRYSTALLOGRAPHIC STRUCTURE DETERMINATION ; HAMSTER OVARY CELLS ; ANTITUMOR-ACTIVITY ; THIENOYL ANTIFOLATE ; SOLID TUMORS ; PHASE-I ; BIOLOGICAL-ACTIVITY ; MOLECULAR-GRAPHICS ; SELECTIVE UPTAKE |
| 资助项目 | National Institutes of Health[CA53535] ; National Institutes of Health[CA125153] ; National Institutes of Health[CA152316] ; National Institutes of Health[CA166711] ; National Institutes of Health[GM094472] ; National Institutes of Health[DK071662] ; National Institutes of Health[GM102545] ; National Institutes of Health[GM104212] ; National Science Foundation[NSF91217311] ; Eunice and Milt Ring Endowed Chair for Cancer Research[00000000] ; Duquesne University Adrian Van Kaam Chair in Scholarly Excellence[00000000] ; Van Andel Research Institute[00000000] ; Ministry of Science and Technology (China)[2012ZX09301001] ; Ministry of Science and Technology (China)[2012CB910403] ; Ministry of Science and Technology (China)[2013CB910600] ; Ministry of Science and Technology (China)[XDB08020303] ; Ministry of Science and Technology (China)[2013ZX09507001] ; NIH Center grant[P30 CA022453] ; Wayne State University[00000000] ; National Institute of General Medical Sciences from the National Institutes of Health[P41 GM103403] ; DOE Office of Science[DE-AC02-06CH11357] ; Michigan Economic Development Corporation[00000000] ; Michigan Technology Tri-Corridor[085P1000817] ; Office of Science of the U.S. Department of Energy[DE-AC02-06CH11357] ; [T32 CA009531] ; [T32 GM007757] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000383111300011 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275895]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Dann, Charles E., III |
| 作者单位 | 1.Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA; 2.Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, 600 Forbes Ave, Pittsburgh, PA 15282 USA; 3.Barbara Ann Karmanos Canc Inst, Mol Therapeut Program, 110 East Warren Ave, Detroit, MI 48201 USA; 4.Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI 48201 USA; 5.Indiana Univ, Dept Chem, Bloomington, IN 47405 USA; 6.Van Andel Res Inst, Lab Struct Sci, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA; 7.Van Andel Res Inst, Lab Struct Biol & Biochem, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA; 8.Chinese Acad Sci, Ctr Struct & Funct Drug Targets, VARI SIMM Ctr, Shanghai Inst Mat Med,Shanghai Inst Biol Sci,Key, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Golani, Lalit K.,Wallace-Povirk, Adrianne,Deis, Siobhan M.,et al. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(17):7856-7876. |
| APA | Golani, Lalit K..,Wallace-Povirk, Adrianne.,Deis, Siobhan M..,Wong, Jennifer.,Ke, Jiyuan.,...&Gangjee, Aleem.(2016).Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.JOURNAL OF MEDICINAL CHEMISTRY,59(17),7856-7876. |
| MLA | Golani, Lalit K.,et al."Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis".JOURNAL OF MEDICINAL CHEMISTRY 59.17(2016):7856-7876. |
入库方式： OAI收割
来源：上海药物研究所
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