ABSTRACT
Quinazolines - 1,3-benzodiazines are biological active compounds, and some of them act as anticancer drugs. We evaluated cytotoxic/antiproliferative activity of new synthetically prepared [1,2,4]triazolo[4,3-c]quinazolines using tumor cell lines HeLa and B16. The in vitro cytotoxic studies of the most active derivative 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin- 4-yl[1,2,4]triazolo[4,3-c]quinazoline (NTCHMTQ) were complemented by cell cycle analysis, and determination of apoptotic DNA fragmentation. Possible direct interaction of NTCHMTQ with calf thymus DNA was tested by the DNA-modified screen-printed electrode. Five quinazoline derivatives tested acted cytotoxically on both tumor cell lines. The melanoma cells B16 were more sensitive to quinazolines treatment than HeLa cells. The most effective derivative was NTCHMTQ which manifested significant in vitro cytotoxic/antiproliferative effect. NTCHMTQ at micromolar concentrations induced morphological changes and necrosis of B16 cells. NTCHMTQ at concentrations tested did not cause changes in cell cycle, did not induce apoptotic cell death in the B16 cells and did not even behave as a typical intercalating agent.
Subject(s)
Antineoplastic Agents/pharmacology , Melanoma, Experimental/drug therapy , Quinazolines/pharmacology , Triazoles/pharmacology , Animals , Cell Death/drug effects , Cell Proliferation/drug effects , DNA Damage , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Inhibitory Concentration 50 , Melanoma, Experimental/pathology , MiceABSTRACT
Quinazolines are multitarget agents, which have broad spectrum of biological activity, and some of them are now in cancer clinical testing. 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline is a new synthetically prepared derivative, which in our previous study showed cytotoxic effects on cancer cell lines HeLa and B16. Quinazoline, at micromolar concentrations, induced morphological changes and necrosis of B16 cells, and at nanomolar concentrations it produced changes of F-actin cytoskeleton. It did not cause changes in the cell cycle, did not induce apoptotic cell death in B16 cells, did not have a mutagenic effect, and did not even behave as a typical intercalating agent. Little significant reduction of tumor volume in intramuscular transplanted B16 cells was observed. The aim of the present study was to examine the cytotoxic effect of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline on murine leukemia L1210 cells and fibroblast NIH-3T3 cells. Induction of cell morphology and cell cycle changes, induction of apoptosis and caspase 3 activity were studied. Quinazoline acted cytotoxically on both cell lines. The sensitivity of leukemia L1210 cells to the quinazoline was higher than that of fibroblast NIH-3T3. The IC(100) was 12 microM for L1210 cells and 24 microM for NIH-3T3 cells. No effect of quinazoline on the cell cycle profile of L1210 and NIH-3T3 was detected, however, quinazoline induced an increase of the sub-G(0) cell fraction, apoptotic DNA fragmentation, and apoptotic morphological changes at a concentration of 12 microM. This quinazoline concentration induced caspase 3 activity. Our results demonstrated that induction of apoptotic cell death via activation of caspase 3 contributed to the cytotoxic effects of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline in murine leukemia L1210 cells.
Subject(s)
Apoptosis/drug effects , Caspase 3/metabolism , DNA Fragmentation/drug effects , Fibroblasts/drug effects , Quinazolines/pharmacology , Triazoles/pharmacology , Animals , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Fibroblasts/metabolism , Mice , Molecular Structure , NIH 3T3 Cells , Quinazolines/chemistry , Time Factors , Triazoles/chemistryABSTRACT
Fifteen substituted 1,2,4-triazolo[4,3-c]quinazolines were tested for antibacterial and antifungal effects. The most effective derivatives had the triazoloquinazoline skeleton substituted with the pharmacologically active chromophores--morpholine, chlorine and nitro group. The broadest antimicrobial activity was found with 5-morpholin-4-yl-3-(5-nitrothien-2-yl)[1,2,4]triazolo[4,3-c]quinazoline in concentration of 10 mg/L for B. subtilis, 50 mg/L for S. aureus and 100 mg/L for C. tropicalis. The highest tested concentration of derivative caused 83% growth inhibition of R. nigricans.
