Tumor-Targeting with Novel Non-Benzoyl 6-Substituted Straight Chain Pyrrolo[2,3-d]pyrimidine Antifolates via Cellular Uptake by Folate Receptor 伪 and Inhibition of de Novo Purine Nucleotide Bio

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• 作者：Yiqiang Wang ; Christina Cherian ; Steven Orr ; Shermaine Mitchell-Ryan ; Zhanjun Hou ; Sudhir Raghavan ; Larry H. Matherly ; Aleem Gangjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8684-8695
• 全文大小：494K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

A new series of 6-substituted straight side chain pyrrolo[2,3-d]pyrimidines 3a鈥?b>d with varying chain lengths (n = 5鈥?) was designed and synthesized as part of our program to provide targeted antitumor agents with folate receptor (FR) cellular uptake specificity and glycinamide ribonucleotide formyltransferase (GARFTase) inhibition. Carboxylic acids 4a鈥?b>d were converted to the acid chlorides and reacted with diazomethane, followed by 48% HBr to generate the 伪-bromomethylketones 5a鈥?b>d. Condensation of 2,4-diamino-6-hydroxypyrimidine 6 with 5a鈥?b>d afforded the 6-substituted pyrrolo[2,3-d]pyrimidines 7a鈥?b>d. Hydrolysis and subsequent coupling with diethyl l-glutamate and saponification afforded target compounds 3a鈥?b>d. Compounds 3b鈥?b>d showed selective cellular uptake via FR伪 and -尾, associated with high affinity binding and inhibition of de novo purine nucleotide biosynthesis via GARFTase, resulting in potent inhibition against FR-expressing Chinese hamster cells and human KB tumor cells in culture. Our studies establish, for the first time, that a side chain benzoyl group is not essential for tumor-selective drug uptake by FR伪.