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Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents
- Source :
- ChemMedChem. 17(1)
- Publication Year :
- 2021
-
Abstract
- Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di- and tri- substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues ( 31a , b ) developed returned average GI 50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N 2 -(3-dimethylaminopropyl)- N 4 -dodecyl-6-methylpyrimidine-2,4-diamine ( 31a ) and N 4 -(3-dimethylaminopropyl)- N 2 -dodecyl-6-methylpyrimidine-2,4-diamine ( 31b ).
- Subjects :
- Dynamins
Pyrimidine
Antineoplastic Agents
Biochemistry
chemistry.chemical_compound
Structure-Activity Relationship
DU145
Prostate
Neuroblastoma
Cell Line, Tumor
Drug Discovery
medicine
Humans
General Pharmacology, Toxicology and Pharmaceutics
Enzyme Inhibitors
Cytotoxicity
Mitosis
Dynamin
Cell Proliferation
Pharmacology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Cytotoxins
Organic Chemistry
medicine.disease
Molecular biology
medicine.anatomical_structure
Pyrimidines
Cell culture
Molecular Medicine
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 18607187
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- ChemMedChem
- Accession number :
- edsair.doi.dedup.....22cf932fa6695301f01d016077b199c8