ABSTRACT
Three new acridine-thiazolidinone derivatives (2a-2c) have been synthesized and their interactions with calf thymus DNA and a number of cell lines (leukemic cells HL-60 and L1210 and human epithelial ovarian cancer cell lines A2780) were studied. The compounds 2a-2c possessed high affinity to calf thymus DNA and their binding constants determined by spectrofluorimetry were in the range of 1.37 × 10(6)-5.89 × 10(6) M(-1). All of the tested derivatives displayed strong cytotoxic activity in vitro, the highest activity in cytotoxic tests was found for 2c with IC(50) = 1.3 ± 0.2 µM (HL-60), 3.1 ± 0.4 µM (L1210), and 7.7 ± 0.5 µM (A2780) after 72 h incubation. The cancer cells accumulated acridine derivatives very fast and the changes of the glutathione level were confirmed. The compounds inhibited proliferation of the cells and induced an arrest of the cell cycle and cell death. Their influence upon cells was associated with their reactivity towards thiols and DNA binding activity.
Subject(s)
Acridines/chemical synthesis , Acridines/pharmacology , DNA/metabolism , Glutathione/metabolism , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Acridines/chemistry , HL-60 Cells , Humans , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Models, Molecular , Thiazolidines/chemistryABSTRACT
New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a-6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-binding of 6a-6e to ctDNA was examined by UV-vis, fluorescence, and CD spectroscopy. The binding constants determined by UV-vis spectroscopy were found in the range 1.9×10(5)-7.1×10(5) M(-1). An electrophoretic separation proved that ligands 6a-6e inhibited topoisomerase I in 40 µM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC(50)=2.12 µM (HL 60) and 5.28 µM (L1210) after 72 h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding.
Subject(s)
Acridines/chemical synthesis , DNA Topoisomerases, Type I/drug effects , Imidazolidines/chemical synthesis , Acridines/chemistry , Acridines/pharmacology , Animals , Cell Line, Tumor , Circular Dichroism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Imidazolidines/chemistry , Imidazolidines/pharmacology , Mice , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , ThermodynamicsABSTRACT
OBJECTIVES: This paper reviews and compares major approaches and strategies to modulation of antioxidative response in the therapy of hypertension and cardiovascular diseases. DESIGN: There are two major strategies of modulation of antioxidative response in hypertension and cardiovascular diseases: (i) modulation of NO levels by NOS stimulation, increase of NO bioavailability, administration of NO, and NOS gene incorporation; (ii) scavenging of superoxide and suppression of oxidative stress by activation of antioxidant gene expression or by suppression of selected genes by RNA silencing. These strategies are accomplished by several concepts, including (1) delivery of external agents, (2) antioxidant gene therapy and RNA silencing, and (3) combined therapies and approaches. CONCLUSION: Combined therapies and approches often achieve multiplicative effects and are the most promising attitude in antioxidant-oriented therapy of hypertension and cardiovascular diseases.
Subject(s)
Antioxidants/metabolism , Antioxidants/pharmacology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/therapy , Hypertension/metabolism , Hypertension/therapy , HumansABSTRACT
A series of acridin-3,6-diyl-dithiourea hydrochloride derivatives (alkyl-AcrDTU) was prepared and tested against sensitive and drug resistant leukemia cell lines for their cytotoxic/cytostatic activity. The products (ethyl-, n-propyl-, n-butyl-, n-pentyl-AcrDTU) showed high DNA binding affinity via intercalation (K=7.6-2.9 x 10(5) M(-1)). All derivatives inhibited proliferation of HL-60 cells and its resistant subline HL-60/ADR, unexpectedly the resistant subline was more sensitive than the parental one (IC(50)=3.5 microM, 48-treatment of HL-60/ADR with pentyl-AcrDTU). Cytotoxicity of tested compounds was associated with their DNA-binding properties and the level of intracellular thiols has been changed in the presence of AcrDTU.
