Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity
| Autor: | Zhanjun Hou, Christina Cherian, Aleem Gangjee, Steven Buck, Larry H. Matherly, Yijun Deng, Yiqiang Wang |
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| Rok vydání: | 2008 |
| Předmět: |
Phosphoribosylglycinamide formyltransferase
Pyrimidine Stereochemistry Antineoplastic Agents Receptors Cell Surface CHO Cells Chemical synthesis KB Cells Article Cell Line Reduced Folate Carrier Protein chemistry.chemical_compound Cricetulus Non-competitive inhibition Cricetinae Drug Discovery Animals Humans Transferase Pyrroles Enzyme Inhibitors Cell Proliferation Phosphoribosylglycinamide Formyltransferase Bicyclic molecule Chemistry Chinese hamster ovary cell Folate Receptors GPI-Anchored Membrane Transport Proteins Pyrimidines Biochemistry Folate receptor Folic Acid Antagonists Molecular Medicine Carrier Proteins |
| Zdroj: | Journal of Medicinal Chemistry. 51:5052-5063 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm8003366 |
| Popis: | 6-Substituted classical pyrrolo[2,3-d]pyrimidine antifolates with a three- to six-carbon bridge between the heterocycle and the benzoyl-L-glutamate (compounds 2-5, respectively) were synthesized starting from methyl 4-formylbenzoate and a Wittig reaction with the appropriate triphenylphosphonium bromide, followed by reduction and conversion to the alpha-bromomethylketones. Cyclocondensation of 2,4-diamino-4-oxopyrimidine with the alpha-bromoketones, coupling with diethyl-L-glutamate, and saponification afforded 2-5. Compounds 2-5 had negligible substrate activity for RFC but showed variably potent (nanomolar) and selective inhibitory activities toward Chinese hamster ovary cells that expressed FRalpha or FRbeta and toward FRalpha-expressing KB and IGROV1 human tumor cells. Inhibition of KB cell colony formation was also observed. Glycinamide ribonucleotide formyl transferase (GARFTase) was identified as the primary intracellular target of the pyrrolo[2,3-d]pyrimidines. The combined properties of selective FR targeting, lack of RFC transport, and GARFTase inhibition resulting in potent antitumor activity are unprecedented and warrant development of these analogues as antitumor agents. |
| Databáze: | OpenAIRE |
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