A synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analoguesElectronic supplementary information (ESI) available. See DOI: 10.1039/c5md00245a

• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c5md00245a

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 GI 50 = 70 nM and a LC 50 = 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 IC 50 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. The thieno[2,3- b ]pyridines bind to TDP1 with the best analogue 9d with IC 50 at 0.5 μM.