Structure鈥揂ctivity Profiles of Novel 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Antifolates with Modified Amino Acids for Cellular Uptake by Folate Receptors 伪 and 尾 and the Proton-Coupled

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• 作者：Lalit K. Golani ; Christina George ; Sai Zhao ; Sudhir Raghavan ; Steven Orr ; Adrianne Wallace ; Mike R. Wilson ; Zhanjun Hou ; Larry H. Matherly ; Aleem Gangjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 9, 2014
• 年：2014
• 卷：57
• 期：19
• 页码：8152-8166
• 全文大小：722K
• ISSN：1520-4804

文摘

Structure鈥揳ctivity relationships for cellular uptake and inhibition of cell proliferation were studied for 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates in which the terminal l-glutamate of the parent structure (7) was replaced by natural or unnatural amino acids. Compounds 7 and 10鈥?b>13 were selectively inhibitory toward folate receptor (FR) 伪-expressing Chinese hamster ovary (CHO) cells. Antiproliferative effects of compounds 7 and 9鈥?b>13 toward FR伪- and FR尾-expressing CHO cells were only partly reflected in binding affinities to FR伪 and FR尾 or in the docking scores with molecular models of FR伪 and FR尾. Compounds 7 and 11 were potent inhibitors of glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis in KB human tumor cells. These studies establish for the first time the importance of the 伪- and 纬-carboxylic acid groups, the length of the amino acid, and the conformation of the side chain for transporter binding and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates.