ABSTRACT
A series of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), HOC(6)H(4)CHN-NHCONR(2), and their rhenium(I) tricarbonyl complexes, [ReBr(CO)(3)(SSC)], have been synthesised and characterised by IR and (1)H NMR spectroscopy. Crystallographic analysis of the complex [ReBr(CO)(3)(H(2)Bu(2))] (H(2)Bu(2)=SSC where R=Bu(n)) showed that the SSC acts as a bidentate ligand via its imino nitrogen and carbonyl oxygen atoms. The [ReBr(CO)(3)(SSC)] complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells (IC(50)=1-24µM, cf. 18µM for cisplatin), and the majority of them are virtually non-toxic against non-cancerous human fibroblasts. Apoptotic assays of [ReBr(CO)(3)(H(2)Bnz(2))] (Bnz=benzyl) revealed that it mediates cytotoxicity in MOLT-4 cells via apoptosis. The complex [ReBr(CO)(3)(H(2)Bnz(2))] reacts with guanosine by proton transfer from the phenolic OH group to N(7) of guanosine. In (CD(3))(2)SO, [ReBr(CO)(3)(H(2)Bnz(2))] undergoes facile conversion to the dimeric complex, [Re(CO)(3)(HBnz(2))](2), via bromide dissociation.
Subject(s)
Aldehydes/chemistry , Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Rhenium/chemistry , Semicarbazones/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Coordination Complexes/pharmacology , Crystallography, X-Ray , Fibroblasts/drug effects , Humans , Magnetic Resonance Spectroscopy , Models, MolecularABSTRACT
The copper(ii) complexes of two salicylaldehyde semicarbazones, HOC(6)H(4)CH[double bond, length as m-dash]N-NHCONR(2) [H(2)Bnz(2) (R = CH(2)Ph) and H(2)Bu(2) (R = Bu)], were evaluated for their DNA binding and cleavage properties by spectrophotometric DNA titration, ethidium bromide displacement assay and electrophoretic mobility shift assay. Results showed that the Cu(ii) complexes can bind to DNA via a partial intercalation mode with binding constants of 1.1 × 10(4) and 9.5 × 10(3) M(-1) for [Cu(HBnz(2))Cl] and [Cu(HBu(2))Cl], respectively. These complexes also cleave DNA in the presence of ascorbic acid, most likely through hydroxyl radicals that are generated via the reduction of a Cu(ii) to a Cu(i) species. The complexes show similar DNA cleavage activity, which is reflected in the similarity of their frontier molecular orbital energies calculated by density functional theory. These results are discussed in relation to the anticancer properties of the complexes.
Subject(s)
Aldehydes/chemistry , Coordination Complexes/chemistry , Copper/chemistry , DNA/chemistry , Semicarbazones/chemistry , Aldehydes/pharmacology , Ascorbic Acid/pharmacology , Cations, Divalent/chemistry , Cations, Divalent/pharmacology , Coordination Complexes/pharmacology , Copper/pharmacology , DNA Cleavage , DNA, Superhelical/chemistry , DNA, Superhelical/genetics , Deoxyribonucleases/chemistry , Deoxyribonucleases/metabolism , Ethidium/pharmacology , Models, Molecular , Plasmids/chemistry , Plasmids/genetics , Semicarbazones/pharmacology , Spectrometry, FluorescenceABSTRACT
The in vitro cytotoxic studies of a series of salicylaldehyde semicarbazones, HOC6H4CH=N-NHCONR2 (H2R2) and their Cu(II) complexes on a number of human tumor cell lines were conducted and it was observed that their cytotoxicities were enhanced following complexation to copper. These copper(II) complexes also demonstrated higher in vitro activities than the reference drug, cisplatin, on the tumor cell lines at micro molar range. Apoptotic assays and cell cycle analysis of the copper complexes, [Cu(HBnz2)Cl] and [Cu(HBu2)Cl] revealed that they mediated cytotoxicity in MOLT-4 cells via apoptosis. Further proteomic investigation of [Cu(HBnz2)Cl] and [Cu(HBu2)Cl] with respect to their protein expression profiles associated with their mode of action was conducted. By comparing the expression levels of 33 identified protein spots amongst the respective compound-treated profiles, we identified similarities in protein expression patterns between the two copper(II) complexes. The possible roles of the identified proteins in the execution of apoptosis by these copper(II) complexes are discussed.
Subject(s)
Aldehydes/toxicity , Copper/toxicity , Organometallic Compounds/toxicity , Proteomics , Semicarbazones/toxicity , Apoptosis/drug effects , Blotting, Western , Cell Cycle/drug effects , Cell Line, Tumor , Crystallography, X-Ray , Flow Cytometry , Humans , Molecular StructureABSTRACT
A novel class of compounds containing N-sulfonylanthranilic acid was found to specifically inhibit dengue viral polymerase. The structural requirements for inhibition and a preliminary structure-activity relationship are described. A UV cross-linking experiment was used to map the allosteric binding site of the compound on the viral polymerase.
