Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis in folate receptor expressing human tumors.

Autor: Wallace-Povirk A; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States., Tong N; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States., Wong-Roushar J; Department of Chemistry, Indiana University, Bloomington, IN 47405, United States., O'Connor C; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States., Zhou X; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States., Hou Z; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States., Bao X; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States., Garcia GE; Department of Chemistry, Indiana University, Bloomington, IN 47405, United States., Li J; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States., Kim S; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States., Dann CE 3rd; Department of Chemistry, Indiana University, Bloomington, IN 47405, United States. Electronic address: cedann@indiana.edu., Matherly LH; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States. Electronic address: matherly@karmanos.org., Gangjee A; Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 May 01; Vol. 37, pp. 116093. Date of Electronic Publication: 2021 Feb 26.
DOI: 10.1016/j.bmc.2021.116093
Abstrakt: 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 FRα or FRβ, the proton-coupled folate transporter or reduced folate carrier, specificity for uptake by FRs was confirmed. Anti-proliferative activities were demonstrated toward FRα-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.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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