ABSTRACT
<p><b>OBJECTIVE</b>To evaluate the antitumor activity of a novel class of 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g]quinazoline-7(6H)-ketones in vitro, and to screen potential anticancer compounds for further study.</p><p><b>METHODS</b>Seventeen compounds of 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g]quinazoline-7(6H)-ketones were synthesized with solid-phase method for biological evaluation of EGFR tyrosine kinase. MTT method was used to evaluate the cytotoxic activity in vitro against three human cancer cell lines (human lung carcinoma cell line A549, human leukemia cell lines K562 and human gastric carcinoma cell line SGC7901).</p><p><b>RESULTS</b>Compound 7-13 and 7-14 showed potent antitumor activities against A549 cells, with IC(50) values of 8.10 and 8.12 mol/L, respectively. Eight compounds showed proliferative inhibition effect on K562 cells, especially 7-2, 7-13 and 7-17, with IC(50) values of 2.22,0.57 and 7.20 mol/L,respectively.And compound 7-13 and 7-3 showed potent antitumor activity against SGC7901 cells, with IC(50) values of 4.20 and 9.71 mol/L, respectively.</p><p><b>CONCLUSION</b>The synthesized compounds 4, 8-Disubstituted-8, 9-dihydropyrazine[2, 3-g] quinazoline-7(6H)-ketones show inhibition effects on human cancer cell lines in vitro. Compound 7-13 has anticancer activity in all three cancer cell lines, which might be used as a potential antitumor drug for further study.</p>
Subject(s)
Humans , Antineoplastic Agents , Chemistry , Pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , K562 Cells , Lung Neoplasms , Pathology , Molecular Structure , Pyrazines , Chemistry , Pharmacology , Quinazolines , Chemistry , Pharmacology , ErbB Receptors , Stomach Neoplasms , Pathology , Structure-Activity RelationshipABSTRACT
<p><b>OBJECTIVE</b>To explore the possible association between activation of rat microsomal glutathione S-transferase 1 (mGST1) and chlorambucil toxicity on selected cancer cell lines.</p><p><b>METHODS</b>Hepatic microsomes were prepared from male Sprague-Dawley rats and washed to remove cytosolic contamination. mGST1 was purified and its activity was measured. PC-3, K562, HepG2 and P388D1 cell lines were exposed to chlorambucil (CHB) alone or to CHB with mGST1 at concentrations of 0 ~ 100 micromol/L for 8, 24, 48, 72 h. Cytotoxic effects of CHB were determined by cell growth inhibition (MTT assay), mitochondrial transmembrane potential (DeltaPsim), and fluorescence morphological examination (AO/EB staining).</p><p><b>RESULTS</b>The decreased cytotoxic effects of CHB on the cell lines altered by mGST1 were demonstrated in concentration- and time-dependant manners. The CHB-induced apoptosis on PC-3 and K562 cell lines altered by mGST1 was confirmed using DeltaPsim examination, JC-1 or AO/EB staining.</p><p><b>CONCLUSION</b>mGST1 can reduce the cytotoxic effects of CHB in selected cancer cell lines.</p>