Synthesis, Biological, and Antitumor Activity of a Highly Potent 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolate Inhibitor with Proton-Coupled Folate Transporter and Folate Receptor

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• 作者：Lei Wang ; Sita Kugel Desmoulin ; Christina Cherian ; Lisa Polin ; Kathryn White ; Juiwanna Kushner ; Andreas Fulterer ; Min-Hwang Chang ; Shermaine Mitchell-Ryan ; Mark Stout ; Michael F. Romero ; Zhanjun Hou ; Larry H. Matherly ; Aleem Gangjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7150-7164
• 全文大小：1114K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1鈥?b>3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-伪-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with l-glutamate diethyl ester, followed by saponification, afforded 1鈥?b>3. Compound 3 selectively inhibited the proliferation of cells expressing folate receptors (FRs) 伪 or 尾, or the proton-coupled folate transporter (PCFT), including KB and IGROV1 human tumor cells, much more potently than 4. Compound 3 was more inhibitory than 4 toward 尾-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1-, 2-, and 4-atom bridge lengths for the activity of this series.