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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
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 mo...
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Main Authors: | , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 2040-2503 2040-2511 |
DOI: | 10.1039/c5md00245a |