3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells
| Autor: | Jóhannes Reynisson, Marina N. Semenova, Leonid D. Konyushkin, Victor V. Semenov, Alex S. Kiselyov, Chatchakorn Eurtivong, Olga P. Atamanenko |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Pyridines Stereochemistry medicine.drug_class Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Carboxamide Microtubules 01 natural sciences Biochemistry Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Microtubule Cell Line Tumor Drug Discovery medicine Animals Humans Colchicine Moiety Molecular Biology Cell Proliferation Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry 0104 chemical sciences 030104 developmental biology Tubulin Mechanism of action chemistry Cell culture Sea Urchins biology.protein Molecular Medicine Drug Screening Assays Antitumor medicine.symptom Growth inhibition |
| Zdroj: | Bioorganic & Medicinal Chemistry. 25:658-664 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.11.041 |
| Popis: | A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50–250 nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket. |
| Databáze: | OpenAIRE |
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