ABSTRACT
2-(1H-Tetrazol-5-yl)pyridine (L) has been reacted separately with Me2NCH2CH2Clâ HCl and ClCH2CH2OH to yield two regioisomers in each case, N,N-dimethyl-2-[5-(pyridin-2-yl)-1H-tetrazol-1-yl]ethanamine (L1)/N,N-dimethyl-2-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]ethanamine (L2) and 2-[5-(pyridin-2-yl)-1H-tetrazol-1-yl]ethanol (L3)/2-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]ethanol (L4), respectively. These ligands, L1-L4, have been coordinated with CuCl2 â H2O in 1 : 1 composition to furnish the corresponding complexes 1-4. EPR Spectra of Cu complexes 1 and 3 were characteristic of square planar geometry, with nuclear hyperfine spin 3/2. Single X-ray crystallographic studies of 3 revealed that the Cu center has a square planar structure. DNA binding studies were carried out by UV/VIS absorption; viscosity and thermal denaturation studies revealed that each of these complexes are avid binders of calf thymus DNA. Investigation of nucleolytic cleavage activities of the complexes was carried out on double-stranded pBR322 circular plasmid DNA by using a gel electrophoresis experiment under various conditions, where cleavage of DNA takes place by oxidative free-radical mechanism (OH(â )). In vitro anticancer activities of the complexes against MCF-7 (human breast adenocarcinoma) cells revealed that the complexes inhibit the growth of cancer cells. The IC50 values of the complexes showed that Cu complexes exhibit comparable cytotoxic activities compared to the standard drug cisplatin.
Subject(s)
Antineoplastic Agents/pharmacology , Copper/pharmacology , DNA/drug effects , Organometallic Compounds/pharmacology , Tetrazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cattle , Cell Survival/drug effects , Copper/chemistry , DNA/chemistry , DNA Cleavage , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Metal ions associated with amyloid-ß (Aß) species have been suggested to be involved in neurodegeneration leading to the progression of Alzheimer's disease (AD). The role of metal-involved Aß species in AD neuropathogenesis, however, is not fully elucidated. In order to advance this understanding and contribute to the therapeutic development for AD, the rational structure-based design of small molecules that specifically target metal ions surrounded by Aß species has recently received increased attention. To date, only a few compounds have been fashioned for this purpose. Herein, we report the design strategy, synthesis, characterization, and reactivity of new bifunctional IMPY derivatives K1 and K2. Using UV-vis and high-resolution two-dimensional (2D) NMR spectroscopy, the bifunctionality of K1 and K2 (metal chelation and Aß interaction) was confirmed. These bifunctional IMPY derivatives showed preferential reactivity toward metal-induced Aß aggregation over metal-free conditions in both in vitro inhibition and disaggregation experiments. Taken together, this study provides another example of a bifunctional small molecule framework that can target metal ions associated with Aß species.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Chelating Agents/chemistry , Chelating Agents/pharmacology , Metals/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/ultrastructure , Drug Design , Humans , Pyrazoles/chemistryABSTRACT
Alpha-chloro ynones have been reduced using Noyori's Ru catalyst to furnish alpha-chloro propargylic alcohols with excellent enantioselectivity. These have been used as a common precursor for the preparation of (E)- and (Z)-2-hydroxy-3,4-unsaturated disubstituted sulfilimines. The latter serve as precursors for the highly regio- and stereoselective preparation of bromo carbamates.
