Title

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

DOI

10.1016/j.bmc.2021.116093

Authors

Adrianne Wallace-Povirk, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
Nian Tong, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
Jennifer Wong-Roushar, Department of Chemistry, Indiana University, Bloomington, IN 47405, United States.
Carrie O'Connor, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
Xilin Zhou, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
Zhanjun Hou, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States.
Xun Bao, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States.
Gloria E. Garcia, Department of Chemistry, Indiana University, Bloomington, IN 47405, United States.
Jing Li, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States.
Seongho Kim, Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, United States.
Charles E. Dann, Department of Chemistry, Indiana University, Bloomington, IN 47405, United States. Electronic address: cedann@indiana.edu.
Larry H. Matherly, 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.
Aleem Gangjee, Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States. Electronic address: gangjee@duq.edu.

Document Type

Journal Article

Publication Date

5-1-2021

Publication Title

Bioorganic & medicinal chemistry

Volume

37

First Page

116093

Abstract

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.

Open Access

Green Accepted

Preprint

Manuscript

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