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Molecules 2014, 19(9), 13076-13092; https://doi.org/10.3390/molecules190913076

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

1
Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), P.O. Box 3660, Riyadh 11481, Kingdom of Saudi Arabia
2
King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia
3
Chemistry Department, Faculty of Science, The University of Jordan, Amman 11942, Jordan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 3 July 2014 / Revised: 12 August 2014 / Accepted: 18 August 2014 / Published: 25 August 2014
(This article belongs to the Section Organic Chemistry)
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Abstract

A selected set of substituted pyridone-annelated isoindigos 3af has been synthesized via interaction of 5- and 6-substituted oxindoles 2af 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. View Full-Text
Keywords: pyridone-annelated isoindigos; 5'-halogeno derivatives; isoindigo; anticancer compounds; antiproliferative activity; apoptosis; K562 cells; THP-1 cells; HepG2 cells; MCF-7 cells; Caco-2 cells; HEK-293 cells; L-929 cells; MTT assay pyridone-annelated isoindigos; 5'-halogeno derivatives; isoindigo; anticancer compounds; antiproliferative activity; apoptosis; K562 cells; THP-1 cells; HepG2 cells; MCF-7 cells; Caco-2 cells; HEK-293 cells; L-929 cells; MTT assay
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Saleh, A.M.; Al-As'ad, R.M.; El-Abadelah, M.M.; Sabri, S.S.; Zahra, J.A.; Alaskar, A.S.; Aljada, A. Synthesis and Biological Evaluation of New Pyridone-Annelated Isoindigos as Anti-Proliferative Agents. Molecules 2014, 19, 13076-13092.

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