Abstract |
Tumor-targeted specificities of 6-substituted pyrrolo[2,3- d] pyrimidine analogues of 1, where the phenyl side-chain is replaced by 3',6' (5, 8), 2',5' (6, 9), and 2',6' (7, 10) pyridyls, were analyzed. Proliferation inhibition of isogenic Chinese hamster ovary (CHO) cells expressing folate receptors (FRs) α and β were in rank order, 6 > 9 > 5 > 7 > 8, with 10 showing no activity, and 6 > 9 > 5 > 8, with 10 and 7 being inactive, respectively. Antiproliferative effects toward FRα- and FRβ-expressing cells were reflected in competitive binding with [3H] folic acid. Only compound 6 was active against proton-coupled folate receptor (PCFT)-expressing CHO cells (∼4-fold more potent than 1) and inhibited [3H] methotrexate uptake by PCFT. In KB and IGROV1 tumor cells, 6 showed <1 nM IC50, ∼2-3-fold more potent than 1. Compound 6 inhibited glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis and showed potent in vivo efficacy toward subcutaneous IGROV1 tumor xenografts in SCID mice.
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Authors | Manasa Ravindra, Adrianne Wallace-Povirk, Mohammad A Karim, Mike R Wilson, Carrie O'Connor, Kathryn White, Juiwanna Kushner, Lisa Polin, Christina George, Zhanjun Hou, Larry H Matherly, Aleem Gangjee |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 61
Issue 5
Pg. 2027-2040
(03 08 2018)
ISSN: 1520-4804 [Electronic] United States |
PMID | 29425443
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antineoplastic Agents
- Folate Receptor 1
- Folate Receptor 2
- Folic Acid Antagonists
- Proton-Coupled Folate Transporter
- Purine Nucleotides
- Pyrimidines
- Pyrroles
- Pyrrolo(2,3-d)pyrimidine
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, pharmacokinetics, pharmacology)
- CHO Cells
- Cell Proliferation
(drug effects)
- Cricetulus
- Folate Receptor 1
(analysis, metabolism)
- Folate Receptor 2
(analysis)
- Folic Acid Antagonists
(chemical synthesis, pharmacology)
- Heterografts
- Humans
- Mice
- Mice, SCID
- Proton-Coupled Folate Transporter
(metabolism)
- Purine Nucleotides
(antagonists & inhibitors)
- Pyrimidines
(chemistry, pharmacokinetics, pharmacology)
- Pyrroles
(chemistry, pharmacokinetics, pharmacology)
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