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1.
Bioorg Chem ; 57: 13-29, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25171773

ABSTRACT

A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G2M-phases of the cell cycle within the first 72h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.


Subject(s)
Acridines/chemistry , Acridines/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA/metabolism , G-Quadruplexes/drug effects , Animals , Cattle , Cell Cycle/drug effects , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/chemistry , Humans , Ligands , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism
2.
Eur J Med Chem ; 57: 283-95, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23072739

ABSTRACT

A series of 3,6-bis(3-alkylguanidino) acridines was prepared and the interaction of these novel compounds with calf thymus DNA was investigated with UV-vis, fluorescence and circular dichroism spectroscopy, in addition to DNA melting techniques. The binding constants K were estimated to range from 1.25 to 5.26 × 10(5) M(-1), and the percentage of hypochromism was found to be 17-42% (from spectral titration). UV-vis, fluorescence and circular dichroism measurements indicated that the compounds act as effective DNA-intercalating agents. Electrophoretic separation proved that ligands 6a-e relaxed topoisomerase I at a concentration of 60 µM, although only those with longer alkyl chains were able to penetrate cell membranes and suppress cell proliferation effectively. The biological activity of novel compounds was assessed using different techniques (cell cycle distribution, phosphatidylserine externalization, caspase-3 activation, changes in mitochondrial membrane potential) and demonstrated mostly transient cytostatic action of the ethyl 6c and pentyl 6d derivatives. The hexyl derivative 6e proved to be the most cytotoxic. Different patterns of cell penetration were also observed for individual derivatives. Principles of molecular dynamics were applied to explore DNA-ligand interactions at the molecular level.


Subject(s)
Acridines/chemical synthesis , Antineoplastic Agents/chemical synthesis , DNA Topoisomerases, Type I/chemistry , DNA/chemistry , Guanidines/chemical synthesis , Intercalating Agents/chemical synthesis , Acridines/pharmacology , Animals , Antineoplastic Agents/pharmacology , Caspase 3/metabolism , Cattle , Cell Cycle/drug effects , Cell Membrane/metabolism , Cell Membrane Permeability , Circular Dichroism , Guanidines/pharmacology , HL-60 Cells , Humans , Intercalating Agents/pharmacology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Molecular Dynamics Simulation , Nucleic Acid Denaturation , Phosphatidylserines/metabolism , Spectrometry, Fluorescence , Structure-Activity Relationship
3.
Bioorg Med Chem ; 19(5): 1790-801, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21315610

ABSTRACT

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 , Thermodynamics
4.
Bioorg Med Chem ; 16(7): 3976-84, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18258438

ABSTRACT

The synthesis of novel 1',1''-(acridin-3,6-diyl)-3',3''-dialkyldiureas was reported. Their biological activity to inhibit cell proliferation was assessed by a MTT assay on two cell lines, HeLa and HCT-116, at micromolar concentration. 1',1''-(Acridin-3,6-diyl)-3',3''-dihexyldiurea hydrochloride was active on a HCT-116 cell line with an IC(50) value of 3.1 microM. The interaction of these compounds with calf thymus DNA was investigated by a variety of spectroscopic techniques including UV-vis, fluorescence and CD spectroscopy. From spectrofluorimetric titrations, binding constants for the DNA-drug complexes were determined (K=0.9-4.2x10(5) M(-1)). Antiproliferative activity of synthesized derivatives might be related to their intercalation into DNA.


Subject(s)
Acridines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , DNA/chemistry , Proflavine/chemistry , Urea/chemical synthesis , Urea/toxicity , Alkylation , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cattle , Cell Line, Tumor , DNA/genetics , Humans , Molecular Structure , Photochemistry , Spectrophotometry , Structure-Activity Relationship , Titrimetry , Urea/chemistry
5.
Bioconjug Chem ; 18(1): 93-100, 2007.
Article in English | MEDLINE | ID: mdl-17226961

ABSTRACT

Five novel proflavine-dithiazolidinone derivatives 4a-4e have been designed and synthesized by the reaction of dialkyl acridin-3,6-diyl dithioureas 3a-3e with methyl bromoacetate. The binding affinity of dithiazolidinone hydrochlorides 5a-5e with calf thymus DNA and plasmid (pUC19) DNA was investigated by a variety of spectroscopic techniques including UV-vis, fluorescence, and CD spectroscopy. The effects of 5a-5e on the thermal denaturation profiles of calf thymus DNA were also studied. From spectrophotometric and spectrofluorimetric titrations, the binding constants for the pUC19 DNA-drug complexes were determined (K = 6.2-2.2 x 104 M-1). In vitro cytotoxic activities of compounds 5a-5e toward murine leukemia cell line L1210 and human uterus carcinoma HeLa cells were also examined. 2',2' '-[(Acridin-3,6-diyl)diimino]-3',3' '-dipropyl-1,3-dithiazolidin-4-one hydrochloride (5b) showed the highest activity against these cells with IC50 values of 6.3 microM and 12.9 microM over the course of 72 h.


Subject(s)
Acridines/chemistry , DNA/chemistry , Proflavine/chemical synthesis , Proflavine/toxicity , Thiazoles/chemistry , Animals , Cattle , Cell Line, Tumor , Cell Shape , Cell Survival/drug effects , Electrons , Humans , Mice , Molecular Structure , Nucleic Acid Denaturation , Photochemistry , Proflavine/chemistry , Spectrum Analysis , Titrimetry , Transition Temperature
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