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Structural tuning of acridones for developing anticancer agents targeting dihydrofolate reductase
- Source :
- Bioorganic & Medicinal Chemistry Letters. 29:126631
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Targeting dihydrofolate reductase, here, we report the tumor growth inhibitory activity of substituted acridones. The screening of the molecules over 60 cell line panel of human cancer cells identified (S)-oxiran-2-ylmethyl 9-oxo-9,10-dihydroacridine-4-carboxylate (19) with average GI50 0.3 μM. The specificity of the compound to CCRF-CEM, MOLT-4 and SR cell lines of leukemia and SW-620, SF268, LOXIMVI, ACHN and MCF7 cancerous cells exhibiting GI50 in the nM range was observed. C6 Glioma cells treated with compound 19 showed differentiated cell morphology and cell cycle arrest in G2/M phase. The interactions of the compound with dihydrofolate reductase were ascertained with the help of enzyme immunoassays, molecular docking and molecular dynamic studies.
- Subjects :
- Models, Molecular
Cell cycle checkpoint
Molecular model
Cellular differentiation
Clinical Biochemistry
Pharmaceutical Science
Antineoplastic Agents
Apoptosis
01 natural sciences
Biochemistry
Structure-Activity Relationship
chemistry.chemical_compound
Drug Discovery
Dihydrofolate reductase
Tumor Cells, Cultured
medicine
Humans
Enzyme Inhibitors
Molecular Biology
Cell Proliferation
Molecular Structure
biology
010405 organic chemistry
Chemistry
Organic Chemistry
Glioma
medicine.disease
0104 chemical sciences
Acridone
Tetrahydrofolate Dehydrogenase
010404 medicinal & biomolecular chemistry
Leukemia
Cell culture
biology.protein
Molecular Medicine
Human cancer
Acridones
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....9bed59f69c4c7eae3f1add8fb1efeaca