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.
Highlights
Leukemia is one of the most fatal hematological cancers worldwide
We show that two of our synthesized compounds having a chlorine and bromine substitution at the 5'-position of the benzo-ring E, effectively inhibit proliferation of K562 cells in a dose- and time-dependent fashion with IC50 values ranging from 4 to
The mass spectra displayed the correct molecular ion peaks for which the measured high-resolution mass spectral (HRMS) data were in good agreement with the calculated values
Summary
Leukemia is one of the most fatal hematological cancers worldwide. Human chronic myelocytic leukemia (CML), a highly common type of leukemia, is a myeloproliferative disorder of blood cells that is characterized by increased proliferation of undifferentiated granulocytic progenitors. CML is induced by constitutive expression and activation of the fusion gene Bcr-Abl encoding a tyrosine kinase, which develops from a translocation between chromosomes 9 and 22 to generate Philadelphia chromosome [1]. Imatinib mesylate (Glivec®), a specific inhibitor of Bcr-Abl activity, was developed as the first anticancer molecule to treat CML patients. A high percentage of CML patients were reported to develop resistance to Glivec® as a result of increased mutation incidents in the Abl kinase domain, indicating the requirement for new treatment regimen [1,2]. In the course of our laboratory studies aiming to synthesize compounds with potential antiproliferative activities towards leukemia cells, we have initiated a chemical synthesis program of indigoid derivatives. Indigoids are a class of bis-indole alkaloids, obtained from Baphicacanthus cusia (Nees) Bremek. (Acanthaceae), Indigofera suffruticosa Mill. (Fabaceae), Indigofera tinctoria L
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