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

Eurtivong, Chatchakorn; Semenov, Victor; Semenova, Marina; Konyushkin, Leonid; Atamanenko, Olga; Reynisson, Jóhannes; Kiselyov, Alex

Abstract

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.

Citation

Eurtivong, C., Semenov, V., Semenova, M., Konyushkin, L., Atamanenko, O., Reynisson, J., & Kiselyov, A. (2017). 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. Bioorganic and Medicinal Chemistry, 25(2), 658-664. https://doi.org/10.1016/j.bmc.2016.11.041

• Journal Article Type: Article
• Acceptance Date: Nov 21, 2016
• Online Publication Date: Nov 29, 2016
• Publication Date: 2017-01
• Deposit Date: Jun 7, 2023
• Journal: Bioorganic & Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 2
• Pages: 658-664
• DOI: https://doi.org/10.1016/j.bmc.2016.11.041
• Keywords: Organic Chemistry; Clinical Biochemistry; Drug Discovery; Pharmaceutical Science; Molecular Biology; Molecular Medicine; Biochemistry
• Additional Information: This article is maintained by: Elsevier; Article Title: 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; Journal Title: Bioorganic & Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.bmc.2016.11.041; Content Type: article; Copyright: © 2016 Elsevier Ltd. All rights reserved.