期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 37, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116093
关键词
-
资金
- National Institutes of Health [R01 CA53535, R01 CA125153, R01 CA152316, R01 CA166711, R01 GM094472]
- Karmanos Cancer Institute
- Eunice and Milton Ring Endowed Chair for Cancer Research
- Duquesne University Adrian Van Kaam Chair in Scholarly Excellence
- DOE Office of Science [DE-AC02-06CH11357]
- NIH Center grant [P30 CA022453]
- [T32 CA009531]
- [F31 CA243215-01]
The study identified first-in-class C1 inhibitors with selective uptake by FRs and dual inhibition of enzyme targets in de novo purine biosynthesis, resulting in anti-tumor activity. This series offers an exciting new platform for selective multi-targeted anti-tumor agents.
We discovered 6-substituted thieno[2,3-d]pyrimidine compounds (3-9) with 3-4 bridge carbons and side-chain thiophene or furan rings for dual targeting one-carbon (C1) metabolism in folate receptor- (FR) expressing cancers. Synthesis involved nine steps starting from the bromo-aryl carboxylate. From patterns of growth inhibition toward Chinese hamster ovary cells expressing FR alpha or FR beta, the proton-coupled folate transporter or reduced folate carrier, specificity for uptake by FRs was confirmed. Anti-proliferative activities were demonstrated toward FR alpha-expressing KB tumor cells and NCI-IGROV1 ovarian cancer cells. Inhibition of de novo purine biosynthesis at both 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase (GARFTase) was confirmed by metabolite rescue, metabolomics and enzyme assays. X-ray crystallographic structures were obtained with compounds 3-5 and human GARFTase. Our studies identify first-in-class C1 inhibitors with selective uptake by FRs and dual inhibition of enzyme targets in de novo purine biosynthesis, resulting in anti-tumor activity. This series affords an exciting new platform for selective multi-targeted anti-tumor agents.
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