A synthesis, in silico, in vitroand in vivostudy of thieno[2,3-b]pyridine anticancer analogues

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 sub(50) = 70 nM and a LC sub(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 sub(50) at 0.5 plus or minus 0.1 mu M. 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.