ABSTRACT
Pyrazolic hybrids appended with naphthalene, p-chlorobenzene, o-phenol and toluene have been synthesized using Claisen Schmidt condensation reaction of 1-benzyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. All compounds were characterized by various spectroscopic techniques. Compound (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(4-chlorophenyl)prop-2-en-1-one crystallizes in monoclinic crystal system with C2/c space group. These synthesized compounds were tested for cytotoxic activity and among these compounds 4b and 5a shows prominent cytotoxic activity against triple-negative breast cancer (TNBC) cells MDA-MB-231 with IC50 values 47.72â µM and 24.25â µM, respectively. Distinguishing morphological changes were noticed in MDA-MB-231 cells treated with pyrazole hybrids contributing to apoptosis action. To get more insight into cytotoxic activity, in silico molecular docking of these compounds were performed and the results suggested that (E)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-1-(p-tolyl)prop-2-en-1-one and 1-(1'-benzyl-5-(4-chlorophenyl)-3',5'-dimethyl-3,4-dihydro-1'H,2H-[3,4'-bipyrazol]-2-yl)ethan-1-one binds to the prominent domain of Akt2 indicating their potential ability as Akt2 inhibitor. Moreover, from inâ silico ADME studies clearly demonstrated that these compounds may be regarded as a drug candidate for sub-lingual absorption based on log p values (2.157-4.924). These compounds also show promising antitubercular activity. The overall results suggest that pyrazolic hybrids with substitution at less sterically hindered positions have appealing potent cytotoxic activity and antituberculosis activity due to which they may act as multidrug candidate.
Subject(s)
Antineoplastic Agents , MDA-MB-231 Cells , Molecular Docking Simulation , Molecular Structure , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Pyrazoles/pharmacology , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
The reaction of aryl imidazo[4,5f] [1,10]phenanthrolines with Cu(NO3)2 lead to the formation of Cu(II) complexes of the type [Cu(L)(NO3)2] where L=PIP, 2-(phenyl) [4,5f] imidazo phenanthroline; HPIP=2-(2-hydroxyphenyl)imidazo [4,5f] phenanthroline and NIP=2-(naphthyl) [4,5f] imidazo phenanthroline. The interaction of these complexes with calf thymus DNA has been studied using viscosity measurements, UV-visible and fluorescence spectroscopy. Chemical nuclease activity of these complexes has also been investigated. All complexes cleave DNA via oxidative pathway involving singlet oxygen. Molecular docking studies revealed that these complexes bind to DNA through minor groove.
Subject(s)
Coordination Complexes/chemistry , Copper/chemistry , DNA/chemistry , Electrochemical Techniques , Imidazoles/chemistry , Molecular Docking Simulation , Phenanthrolines/chemistry , Singlet Oxygen/chemistryABSTRACT
Two new zinc(ii) complexes, [Zn(l-His)(NIP)]+(1) and [Zn(acac)2(NIP)](2) (where NIP is 2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, acac = acetyl acetone), have been synthesized and characterized by elemental analysis, UV-vis, fluorescence, IR, 1H NMR and electron spray ionization mass spectroscopies. Gel retardation assay, atomic force microscopy and dynamic light scattering studies show that 1 and 2 can induce the condensation of circular plasmid pBR322 DNA into nanometer size particles under ambient conditions. Treatment of 2 with 5 mM EDTA restored 30% of the supercoiled form of DNA, revealing partial reversibility of DNA condensation. The in vitro transfection experiment demonstrates that the complexes can be used to deliver pCMV-tdTomato-N1 plasmid which expresses red fluorescent protein. The confocal studies show that the fluorescent nature of complexes is advantageous for visualizing the intracellular delivery of metal complexes as well as transfection efficiency using two distinct emission windows.
Subject(s)
Coordination Complexes/chemistry , DNA, Circular/administration & dosage , Fluorescent Dyes/chemistry , Plasmids/administration & dosage , Transfection/methods , Zinc/chemistry , DNA, Circular/genetics , Gene Expression , Gene Transfer Techniques , Humans , Imidazoles/chemistry , Luminescent Proteins/genetics , MCF-7 Cells , Microscopy, Confocal , Naphthalenes/chemistry , Optical Imaging , Phenanthrolines/chemistry , Plasmids/genetics , Red Fluorescent ProteinABSTRACT
An efficient route was developed for synthesis of bicyclic benzimidazole nucleosides from readily available d-glucose. The key reactions were Vörbruggen glycosylation and ring closing metathesis (RCM). Primarily, to understand the mode of DNA binding, we performed a molecular docking study and the binding was found to be in the minor groove region. Based on the proposed binding model, UV-visible and fluorescence spectroscopic techniques using calf thymus DNA (CT-DNA) demonstrated a non-intercalative mode of binding. Antiproliferative activity of nucleosides was tested against MCF-7 and MDA-MB-231 breast cancer cell lines and found to be active at low micromolar concentrations. Compounds and displayed significant antiproliferative activity as compared to and with the reference anticancer drug, doxorubicin. Cell cycle analysis showed that nucleoside induced cell cycle arrest at the S-phase. Confocal microscopy has been performed to validate the induction of cellular apoptosis. Based on these findings, such modified bicyclic benzimidazole nucleosides will make a significant contribution to the development of anticancer drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , DNA, Neoplasm/drug effects , Nucleosides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Binding Sites/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Molecular Docking Simulation , Nucleosides/chemical synthesis , Nucleosides/chemistry , Structure-Activity RelationshipABSTRACT
The thiosemicarbazone derivative of anthracene (ATSC, anthracene thiosemicarbazone 1) and its copper(II) complex (CuATSC, 2) were synthesized and characterized by spectroscopic, electrochemical, and crystallographic techniques. Interaction of 1 and 2 with calf thymus (CT) DNA was explored using absorption and emission spectral methods, and viscosity measurements reveal a partial-intercalation binding mode. Their protein binding ability was monitored by the quenching of tryptophan emission using bovine serum albumin (BSA) as a model protein. Furthermore, their cellular uptake, in vitro cytotoxicity testing on the HeLa cell line, and flow cytometric analysis were carried out to ascertain the mode of cell death. Cell cycle analysis indicated that 1 and 2 cause cell cycle arrest in sub-G1 phase.
Subject(s)
Antineoplastic Agents/pharmacology , Copper/chemistry , Fluorescence , Organometallic Compounds/pharmacology , Thiosemicarbazones/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Death/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Ligands , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
The thiosemicarbazide derivative of anthracene, ATSC, has been synthesized and characterized by elemental analysis, IR, UV-visible, (1)H NMR, fluorescence, and mass spectroscopy experiments. The interaction of hydrated electron (e(-)aq) with ATSC proceeds via radical anion formation followed by intramolecular transfer that cleaves the thiosemicarbazide side chain on the anthracene moiety. HPLC and ESI-MS experiments suggested that the anthrylmethyl radical combines with different ATSC fragments during the reaction. ATSC, its one-electron reduction products, and dimers were analyzed combining experiments with density functional theory.
