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Synthesis and Biological Evaluation of New Pyridone-Annelated Isoindigos as Anti-Proliferative Agents

Authors :
Ayman M. Saleh
Randa M. Al-As'ad
Mustafa M. El-Abadelah
Salim S. Sabri
Jalal A. Zahra
Ahmed S. Alaskar
Ahmad Aljada
Source :
Molecules, Vol 19, Iss 9, Pp 13076-13092 (2014)
Publication Year :
2014
Publisher :
MDPI AG, 2014.

Abstract

A selected set of substituted pyridone-annelated isoindigos 3a–f has been synthesized via interaction of 5- and 6-substituted oxindoles 2a–f with 6-ethyl-1,2,9-trioxopyrrolo[3,2-f]quinoline-8-carboxylic acid (1) in acetic acid at reflux. Among these isoindigos, the 5'-chloro and 5'-bromo derivatives 3b and 3d show strong and selective antiproliferative activities against a panel of human hematological and solid tumor cell-lines, but not against noncancerous cells, suggesting their potential use as anticancer agents. In all the tested cell lines, compound 3b was a 25%–50% more potent inhibitor of cell growth than 3d, suggesting the critical role of the substitution at 5'-position of the benzo-ring E. The IC50 values after 48 hours incubation with the 5'-chloro compound 3b were 6.60 µM in K562, 8.21 µM in THP-1, 8.97 µM in HepG2, 11.94 µM in MCF-7 and 14.59 µM in Caco-2 cancer cells, while the IC50 values in noncancerous HEK-293 and L-929 were 30.65 µM and 40.40 µM, respectively. In addition, compound 3b induced higher levels apoptosis in K562 cells than 3d, as determined by annexin V/7-AAD flowcytometry analysis. Therefore, further characterization of the antitproliferative mechanisms of compounds 3b and 3d may provide a novel chemotherapeutic agents.

Details

Language :
English
ISSN :
14203049
Volume :
19
Issue :
9
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.f70c9af71b1343bc9bb01d619b6be224
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules190913076