Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
| Autor: | Paola Oliva, Romeo Romagnoli, Elena Mariotto, Luisa Carlota Lopez-Cara, Salvatore Ferla, Maria Kimatrai Salvador, Elena Mattiuzzo, Andrea Brancale, Mariem Chayah, Filippo Prencipe, Ernest Hamel, Giampietro Viola, Roberto Ronca, Roberta Bortolozzi, Santiago Schiaffino Ortega, Stefania Baraldi, Pier Giovanni Baraldi |
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| Rok vydání: | 2019 |
| Předmět: |
Drug Evaluation
Preclinical Apoptosis Microtubules 01 natural sciences Polymerization chemistry.chemical_compound Pyrimidine analogue derivates Drug Discovery Epidermal growth factor receptor vascular disrupting agents tyrosine kinase EGFR inhibitors colchicine site lung cancer tubulin anticancer thienopyrimidine discovery derivates Membrane Potential Mitochondrial 0303 health sciences biology Kinase Cell Cycle tyrosine kinase thienopyrimidine ErbB Receptors Biochemistry vascular disrupting agents Molecular Medicine Poly(ADP-ribose) Polymerases Tyrosine kinase Pyrimidine macromolecular substances anticancer NO 03 medical and health sciences Enzyme activator Microtubule Cell Line Tumor colchicine site Humans Cell Proliferation 030304 developmental biology EGFR inhibitors Drug Discovery3003 Pharmaceutical Science Vascular Endothelial Growth Factor Receptor-2 0104 chemical sciences Enzyme Activation lung cancer 010404 medicinal & biomolecular chemistry Pyrimidines Tubulin tubulin chemistry Drug Design biology.protein Colchicine Reactive Oxygen Species discovery HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 62:1274-1290 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01391 |
| Popis: | The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase. |
| Databáze: | OpenAIRE |
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