A synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analogues

Arabshahi, Homayon J.; van Rensburg, Michelle; Pilkington, Lisa I.; Jeon, Chae Yeon; Song, Mirae; Gridel, Ling-Mey; Leung, Euphemia; Barker, David; Vuica-Ross, Milena; Volcho, Konstantin P.; Zakharenko, Alexandra L.; Lavrik, Olga I.; Reynisson, Jóhannes

Abstract

The anticancer activity of the thieno[2,3-b]pyridines was explored by altering the ring size of the cyclo-aliphatic moiety. Five-, six-, seven- and eight-membered derivatives were tested against the NCI60 tumour cell panel. According to this assay the most active derivative 9a has a cyclooctane moiety, which suggests that larger aliphatic ring systems are favourable. For the most sensitive tumour cell line MB-MDA-435, derivative 9a has a GI50 = 70 nM and a LC50 = 925 nM. To explore the biological mechanism of the thieno[2,3-b]pyridines five derivatives were tested against tyrosyl-DNA phosphodiesterase I (TDP1), a phospholipase D enzyme, using a biochemical assay. The most potent derivative for TDP1 was 9d, giving an excellent IC50 at 0.5 ± 0.1 μM. Also, derivative 12 was tested against 97 kinases and no or very limited activity was found, excluding this class of biomolecular targets. Finally, a mouse xenograft study using derivative 12 was encouraging but the tumour size/mass reduction was not quite statistically significant.

Citation

Arabshahi, H. J., van Rensburg, M., Pilkington, L. I., Jeon, C. Y., Song, M., Gridel, L., …Reynisson, J. (in press). A synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analogues. MedChemComm, 6(11), 1987-1997. https://doi.org/10.1039/c5md00245a

• Journal Article Type: Article
• Acceptance Date: Sep 9, 2015
• Online Publication Date: Sep 22, 2015
• Deposit Date: Jun 7, 2023
• Journal: MedChemComm
• Print ISSN: 2040-2503
• Electronic ISSN: 2040-2511
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 11
• Pages: 1987-1997
• DOI: https://doi.org/10.1039/c5md00245a
• Keywords: Pharmaceutical Science; Biochemistry; Drug Discovery; Molecular Medicine; Pharmacology; Organic Chemistry
• Additional Information: : This document is Similarity Check deposited; : Supplementary Information; : The Royal Society of Chemistry has an exclusive publication licence for this journal; OPEN ACCESS: The accepted version of this article will be made freely available after a 12 month embargo period; : Single-blind; : Received 8 June 2015; Accepted 9 September 2015; Accepted Manuscript published 22 September 2015; Advance Article published 6 October 2015; Version of Record published 4 November 2015