Characterization of the potency of epidermal growth factor (EGFR)-DNA targeting combi-molecules containing a hydrolabile carbamate at the 3-position of the triazene chain
| Autor: | Gina Belinsky, Bertrand J. Jean-Claude, Qiyu Qiu, Margarita Todorova, Meaghan MacPhee, Zakaria Rachid |
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| Rok vydání: | 2010 |
| Předmět: |
Carbamate
DNA damage medicine.medical_treatment Antineoplastic Agents Mice chemistry.chemical_compound Drug Stability Epidermal growth factor In vivo Cell Line Tumor medicine Animals Humans Pharmacology (medical) Phosphorylation Triazene Protein Kinase Inhibitors Cell Proliferation Enzyme Assays EGFR inhibitors Pharmacology Dose-Response Relationship Drug Epidermal Growth Factor Chemistry Hydrolysis Cell Cycle DNA Neoplasm Flow Cytometry ErbB Receptors Microscopy Fluorescence Oncology Biochemistry Carbamates Triazenes Growth inhibition DNA DNA Damage Protein Binding |
| Zdroj: | Investigational New Drugs. 29:833-845 |
| ISSN: | 1573-0646 0167-6997 |
| DOI: | 10.1007/s10637-010-9431-5 |
| Popis: | Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation. Their half-lives were prolonged by ca 20-55 min when compared with their acetoxymethyltriazene counterparts. While they decomposed slowly in serum-containing medium, their intracellular decomposition was extremely rapid. They blocked EGFR tyrosine kinase in an isolated enzyme assay and in MDA-MB-468 breast cancer cells. Similarly, they all induced a dose-dependent DNA damage and G2/M cell cycle arrest in MDA-MB-468 cells, except the most stable compound ZRL2 (a 3-vinyl carbamate). ZRL4 (a chloromethyl carbamate) was the most potent and ZRL2 was the least active of the series against MDA-MB-468 cells. In selectivity assay with NIH-3T3 and NIH-3T3/HER-14, all compounds selectively blocked proliferation of NIH-3T3/HER-14. ZRS1 exerted the strongest growth inhibitory potency of the series. The results in toto suggest that ZRL2, despite being the most stable compound, could not hydrolyze at a rate that permitted the generation of DNA damaging species, thereby behaving primarily as an EGFR inhibitor. Thus the study permitted the definition of an optimized combi-molecule as one that decomposes at a rate that is slower than that of acetoxymethyltriazenes, but rapid enough to generate strong EGFR-DNA targeting potential and growth inhibition. Based on the latter criteria, ZRS1 and ZRL4 were tested in vivo and ZRS1 has proven the more effective. |
| Databáze: | OpenAIRE |
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