Discovery of 5-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates as Dual-Acting Inhibitors of Glycinamide Ribonucleotide Formyltransferase and 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase in De Novo Purine Nucleotide Biosynthesis: Implications of Inhibiting 5-Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase to AMPK Activation and Antitumor Activity
| Autor: | Aleem Gangjee, Manasa P. Ravindra, Shermaine Mitchell-Ryan, Larry H. Matherly, Steven Orr, Eric C. Hales, Sudhir Raghavan, Christina Cherian, Zhanjun Hou, Yiqiang Wang |
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| Rok vydání: | 2013 |
| Předmět: |
Hydroxymethyl and Formyl Transferases
Models Molecular Ribonucleotide medicine.drug_class AICA ribonucleotide Antineoplastic Agents Apoptosis Carboxamide CHO Cells AMP-Activated Protein Kinases KB Cells Article Structure-Activity Relationship chemistry.chemical_compound Cricetulus Drug Discovery medicine Animals Humans Pyrroles Enzyme Inhibitors Purine Nucleotides Cell Proliferation Dose-Response Relationship Drug Molecular Structure Chinese hamster ovary cell Adenosine Pyrimidines chemistry Biochemistry Antifolate Folic Acid Antagonists Molecular Medicine Drug Screening Assays Antitumor Growth inhibition Thymidine medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 56:10016-10032 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm401328u |
| Popis: | We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5-10) with one-to-six bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analogue and potently inhibited proliferation of folate receptor (FR) α-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FRα is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Antiproliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action. |
| Databáze: | OpenAIRE |
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