Synthesis of new thienylpicolinamidine derivatives and possible mechanisms of antiproliferative activity
Three thienylpicolinamidine derivatives 4a-c were prepared from their corresponding picolinonitriles 3a-c on treatment with lithium trimethylsilylamide, LiN(TMS) 2 , followed by a de-protection step using ethanol/HCl (gas). DFT calculations were used to optimize the geometric structure of the newly...
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Veröffentlicht in: | RSC advances 2020-11, Vol.1 (67), p.41165-41176 |
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Zusammenfassung: | Three thienylpicolinamidine derivatives
4a-c
were prepared from their corresponding picolinonitriles
3a-c
on treatment with lithium trimethylsilylamide, LiN(TMS)
2
, followed by a de-protection step using ethanol/HCl (gas). DFT calculations were used to optimize the geometric structure of the newly synthesized picolinamidines. The comparison of DFT calculated spectral data with the experimental data (
1
H-NMR and
13
C-NMR) showed a good agreement. The
in vitro
antiproliferative activity of the cationic compounds
4a-c
was determined against 60 cancer cell lines representing nine types of cancer. The tested picolinamidines were highly active with compounds
4a
and
4b
eliciting mainly cytotoxic activity with GI values ranging from −7.17 to −86.03. Leukemia (SR and K-562), colon (SW-620 and HT29), and non-small cell lung cancer (NCI-H460) cell lines were the most responsive to the investigated picolinamidines. In particular, 4-methoxyphenyl derivative
4a
showed a profound growth deterring power with GI
50
of 0.34 μM against SR, 0.43 μM against SW-620, and 0.52 μM against NCI-H460. The three tested picolinamidines elicited potent GI
50
values against all tested cell lines at low micromolar to sub-micromolar level. The new picolinamidines were selective and did not affect normal human fibroblasts. The selectivity index ranged from 13-21 μM. The novel picolinamidines downregulated the expression of key genes in the cell cycle,
cdk1
and
topoII
, but did not affect
p53
or
txnrd1
. Compounds
4b
and
4c
caused a significant reduction in the concentrations of TopoII and MAPK proteins but were devoid of any effect on the activity of caspase 3. Taken together, these promising anticancer candidates are effective at very low concentrations and safe to normal cells, and most probably work through arresting the cell cycle, and therefore, they deserve further investigations.
Three thienylpicolinamidine derivatives
4a-c
were prepared from their corresponding picolinonitriles
3a-c
on treatment with lithium trimethylsilylamide, LiN(TMS)
2
, followed by a de-protection step using ethanol/HCl (gas). |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/d0ra08796c |