6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor 伪 and the Proton-Coupled Folate Transporter in Human Tumors

详细信息    查看全文

• 作者：Lei Wang ; Adrianne Wallace ; Sudhir Raghavan ; Siobhan M. Deis ; Mike R. Wilson ; Si Yang ; Lisa Polin ; Kathryn White ; Juiwanna Kushner ; Steven Orr ; Christina George ; Carrie O鈥機onnor ; Zhanjun Hou ; Shermaine Mitchell-Ryan ; Charles E. Dann ; III ; Larry H. Matherly ; Aleem Gangjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6938-6959
• 全文大小：936K
• ISSN：1520-4804

文摘

2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) 伪 or 尾 (IC₅₀s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC₅₀ < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FR伪 and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FR伪 and 尾 over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting.