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. Issue 2 (15th January 2017)

• Record Type: Journal Article
• Authors: Eurtivong, Chatchakorn; Semenov, Victor; Semenova, Marina; Konyushkin, Leonid; Atamanenko, Olga; Reynisson, Jóhannes; Kiselyov, Alex
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 2(2017)
• Page Start: 658
• Page End: 664
• Publication Date: 2017-01-15
• Subjects: Microtubule-destabilisation -- Sea urchin embryo assay -- Anticancer -- Thieno[2, 3-b]pyridines -- Molecular modelling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.11.041
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: The thieno[2, 3- b ]pyridines are shown to induce microtubule-destabilisation explaining their efficacy against cancer cells. 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.