Complexation of drug amifampridine with Cu(II), Zn(II) and Cd(II) ions, and its dimerization with the magic of Mn(II) salts. Potential anti-COVID-19 and anticancer activities.

The different behaviors of the drug amifampridine (AMP) against Mn(II), Cu(II), Zn(II) and Cd(II) metal ions, in the presence and absence of tris(2-aminoethyl)amine (tren) was studied. The results showed that AMP successfully coordinates with Cu(II), Zn(II) and Cd(II) metal ions, but interestingly it undergoes an unexpected dimerization through a C-H activation in the presence of different Mn(II) salts. A four-coordinate complex of zinc(II), [Zn(AMP)2Cl2] (1), a binuclear complex of cadmium(II), [Cd2(AMP)2Cl4] (2), three five-coordinate tren-based metal complexes, [Cu(tren)(AMP)](ClO4)2 (8), [Zn(tren)(AMP)]Cl2 (9) and [Cd(tren)(AMP)](ClO4)2 (10), three pyridinium salts, [AmpDimer]X (X = Cl-, NO3-, ClO4-; (3, 4 & 5)), and also two four-coordinate metal complexes with this pyridinium cation, [Zn(AmpDimer)Cl3] (6) and [Cd(AmpDimer)Cl3] (7), were synthesized. All new compounds were characterized by elemental analysis and IR spectroscopy, and by 1H- and 13C-NMR spectroscopy (for 1, 2, 3, 6, 7, 9 & 10) and by X-ray crystal structure determinations (for 1, 3, 4, 5, 7, 8 & 10). Theoretical studies showed that the [M(tren)(AMP)]2+ cations act as pH-sensitive drug carriers of AMP and release it upon protonation. The molecular docking studies on the interaction of AMP and the above complexes/salts with DNA and the proteins of SARS-CoV-2 showed that the synthesized complexes/salts have greater anticancer and anti-covid-19 activities than AMP alone.

Catalysis of the Nitroso-Diels-Alder cycloaddition reaction between CH3N=O and cis-1,3-butadiene by pnictogen bonding, a theoretical study.

Density functional theory calculations at the M06-2X/aug-cc-pVTZ level of theory have been used to examine the Nitroso-Diels-Alder (N-D-A) cycloaddition reaction between the CH3N=O and cis-1,3-butadiene in the presence of PO2X (X=F, Cl, OH) as a catalyst. The effect of the above PO2X compounds on the activation energy of the N-D-A reaction, has been studied here. In the first stage, the energies of two different bonding interactions, via P⋯N versus P⋯O binding, between the PO2X and CH3N=O molecules were calculated. The results showed that the largest values of the interaction energy between the above molecules belong to the PO2F, when connects to the nitrogen atom of the CH3N=O. Also, calculations showed that all the above PO2X compounds, decrease the activation energies of N-D-A reaction studied here via both P⋯N and P⋯O interactions. However, the largest effect on activation energies of the reaction belongs to the PO2F catalyst when acts via P⋯N bonding. The activation strain model (ASM) was used to analyze the influence of the PO2X catalyst on the studied reaction. The quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis were performed to understand the nature of forming interactions at the TS structures. The results of this study showed that the PO2X (X=F, Cl, OH) compounds may be suggested as efficient catalysts for N-D-A reactions.

The Use of Molecular Docking and Spectroscopic Methods for Investigation of The Interaction Between Regorafenib with Human Serum Albumin (HSA) and Calf Thymus DNA (Ct-DNA) In The Presence Of Different Site Markers.

BACKGROUND: Interactions of drugs with DNA and proteins may modify their biological activities and conformations, which effect transport and biological metabolism of drugs. OBJECTIVE: In this study the interaction of anticancer drug regorafenib (REG) with calf thymus-DNA (ct-DNA) and human serum albumin (HSA) has been investigated Methods: Hence, for the first time, it was discovered interaction between REG with DNA and HSA using multi-spectroscopic, zeta potential measurements and molecular docking method. RESULTS AND DISCUSSION: DNA displacement studies showed that REG does not have any effect on acridine orange and methylene blue bound DNA, though it was substantiated by displacement studies with Hoechst (as groove binder). Furthermore, the different concentrations of REG induce slight changes in the viscosity of ct-DNA. Zeta potential parameters indicated that hydrophobic interaction plays a major role in the DNA-REG complex. Results obtained from molecular docking demonstrate that the REG prefers to bind on the minor groove of DNAs than that of the major groove. Binding properties of HSA reveal that intrinsic fluorescence of HSA could be quenched by REG in a static mode. The competitive experiments in the presence of warfarin and ibuprofen (as site markers) suggested that the binding site of REG to HSA was most probably located in the subdomain IIA. Measurements of the zeta potential indicated that REG bound to HSA mainly by both electrostatic and hydrophobic interactions. It was found on docking procedures that REG could fit well into HSA subdomain IIA, which confirmed the experimental results. CONCLUSION: In conclusion, REG can be delivered by HSA in a circulatory system and affect DNA as potential target.

Preparation of a highly stable drug carrier by efficient immobilization of human serum albumin (HSA) on drug-loaded magnetic iron oxide nanoparticles.

Albumin immobilized nanoparticles are known to be biodegradable, easy to prepare and reproducible for drug delivery systems. In summary, we have synthesized a new drug carrier using modified iron oxide nanoparticles. The synthesized drug carrier was characterized by X-ray powder diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), Fourier transform infrared (FT-IR), vibrating sample magnetometry (VSM) and energy-dispersive X-ray spectroscopy (EDX). Three different drugs were loaded on the modified iron oxide nanoparticles and then human serum albumin (HSA) immobilized on the iron oxide nanoparticles. In addition, the in-vitro antiproliferative activity of Fe3O4@SiO2@Nev@HSA nanoparticles against Hela cancer cell line using MTT colourimetric assay was compared with nevirapine. The results show that Fe3O4@SiO2@Nev@HSA nanoparticles in comparison to nevirapine itself have more effective antiproliferative activity on Hela cancer cell lines. The IC50 value for Fe3O4@SiO2@Nev@HSA nanoparticles was 59.20 µg/ml, which is close to the antiproliferative activity of anti-cancer gefitinib with IC50 value of 76.24 µg/ml. Moreover, in vitro calf thymus DNA (ct-DNA) binding studies were investigated by various spectroscopy techniques.

Binding site identification of anticancer drug gefitinib to HSA and DNA in the presence of five different probes.

This study was carried out to evaluate the binding interaction of gefitinib (GEF) with human serum albumin (HSA) and calf thymus DNA (ct-DNA) using fluorescence, UV-Visible, zeta potential measurements and molecular docking methods in order to understand its pharmacokinetic mechanism. By increasing the temperature, a steady decrease in Stern-Volmer quenching constants was observed for HSA binding properties; this indicates a static type of fluorescence quenching. Negative values were calculated for Gibbs free energy (ΔG), enthalpy (ΔH), and entropy (ΔS) changes, indicating that the reaction is spontaneous and enthalpy-driven. Probe competitive experimental results showed that GEF contains the same binding site as warfarin and are consistent with modeling results. The zeta potential of the HSA increased with increasing GEF, which represents the presence of electrostatic interactions in the system. DNA binding properties were investigated in the presence of three probes. The experimental results showed that by increasing GEF to DNA-AO (acridine-orange) and DNA-MB (methylene-blue) system, the fluorescence intensity and absorbance spectra had no considerable change. Furthermore, with the addition of GEF to DNA, the zeta potential decreased gradually, indicating that the hydrophobic interaction between the GEF and the bases of DNA is the major factor. Thus, GEF can bind to DNA via a groove binding mode. It was also found that GEF entered into the minor groove in the A-T rich region of DNA fragment and bind via van der-Waals forces and three H-bond with double strands of DNA. This is in good agreement with experimental results.

Anticancer activity, calf thymus DNA and human serum albumin binding properties of Farnesiferol C from Ferula pseudalliacea.

In this study, Farnesiferol C was introduced as an anti-colon cancer agent. Its cytotoxicity was investigated on two cancer cell lines, HCT116 and CT26, and mesenchymal stem cells (MSCs) as normal cells employing MTT assay. Moreover, Farnesiferol C interactions with ct-DNA and HSA were investigated by various techniques. The IC50 values of Farnesiferol C on HCT116 and CT26 cells were 42 and 46 µM, respectively, while its IC50 value on MSCs cells was 92 µM, indicating that Farnesiferol C was more efficacious against cancer cell lines than normal cells. DNA competitive binding studies, viscosity and zeta potential measurements confirmed that Farnesiferol C bound to DNA through intercalation binding. HSA binding investigations revealed that there were two different binding sites for Far C on HSA with higher binding affinity in site 2 compared to site 1. Furthermore, Farnesiferol C could bind to HSA and quench its intrinsic fluorescence in a static quenching mechanism, with a distance of 2.54 nm. Competitive binding in the presence of warfarin and ibuprofen was carried out and the resulting quenching constant was strongly changed in the presence of warfarin. Consequently, Farnesiferol C most probably will be located within sub-domain IIA. In this study, molecular modeling buttressed and confirmed our laboratory results. Conclusively, we proposed that DNA is an appropriate target for Farnesiferol C. Therefore, Farnesiferol C and its semisynthetic analogues can be one of the priority innovations in research on anticancer drugs.

In vitro cytotoxicity and DNA/HSA interaction study of triamterene using molecular modelling and multi-spectroscopic methods.

The anticancer activity of triamterene on HCT116 and CT26 colon cancer cells lines was investigated. Furthermore, the mechanism of interaction between triamterene and calf thymus DNA (ct-DNA) and also human serum albumin (HSA) was conducted using spectroscopic and molecular docking techniques. In vitro cytotoxicity of triamterene against HCT116 and CT26 cells showed promising anticancer effects with IC50 values of 31.30 and 24.45 µM, respectively. Competitive studies of the triamterene with NR (neutral red) and MB (methylene blue) as intercalator probes showed that triamterene can be replaced by these probes. The viscosity data also confirmed that triamterene binds to calf-thymus DNA through intercalation binding mode. Binding properties of triamterene with HSA in the presence of warfarin and ibuprofen showed that triamterene competes with warfarin for the site I of human serum albumin (HSA). In addition, the binding modes of triamterene with DNA and HSA were verified by molecular docking technique. Abbreviations ct-DNA calf thymus DNA CV cyclic voltammetry DNA deoxyribonucleic acid DPV differential pulse voltammetry FBS fetal bovine serum HSA human serum albumin NR neutral red MB methylene blue MTT 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide Communicated by Ramaswamy H. Sarma.

Improving antiproliferative effect of the nevirapine on Hela cells by loading onto chitosan coated magnetic nanoparticles as a fully biocompatible nano drug carrier.

The freshly prepared magnetic iron oxide nanoparticles (MIONPs) were coated with SiO2 and then modified with a Si-based linker (SiL) having chlorine atom at the end of its chain. The resulting chlorine functionalized MIONPs were bonded to chitosan (CT) in trimethylamine solution. Then nevirapine (Nev) drug was loaded into above CT-SiL-MIONPs system and resulting Nev-loaded magnetic nanoparticles, Nev@CT-SiL-MIONPs, studied using different techniques. Furthermore, the value of Nev loading efficiency and also controlled delivery effect of Nev@CT-SiL-MIONP particles was determined by UV-vis spectrometer. Interestingly, the above nanomaterial showed a superparamagnetic property with a saturation magnetization value of 35.66 emu/g, indicating that it has an excellent potential application in the treatment of cancer using magnetic targeting drug delivery technology. Furthermore, the in-vitro antiproliferative activity of Nev@CT-SiL-MIONPs against cancer cell line (Hela) was compared with nevirapine using MTT colourimetric assay. The Nev-loaded magnetic nanoparticles were shown to be more effective antiproliferative on Hela cancer cell lines than nevirapine itself. Moreover, in vitro ct-DNA binding studies were investigated by UV-Vis and competitive fluorescence spectroscopies. The results showed that DNA aggregated on Nev-loaded nanoparticles via groove binding mode.

Pd(II) and Pd(IV) complexes with 5-methyl-5-(4-pyridyl)hydantoin: synthesis, physicochemical, theoretical, and pharmacological investigation.

The reaction of K2[PdCl4] and PdCl2 with 5-methyl-5-(4-pyridyl)-2,4-imidazolidenedione (L) proceeded with the formation of two different Pd complexes, PdL2Cl2 (1) and PdL2Cl4 (2c), corresponded to a substitution reaction and a substitution reaction along with unanticipated oxidation, respectively. The nature of the oxidizing agent is unknown. These compounds have been studied by elemental analysis, IR, (1)H and (13)CNMR, molar conductivity, and cyclic voltammetry. In addition, structural optimization by DFT calculations and simulation of NMR spectra have been performed and compared with the experimental data. NBO analysis, HOMO and LUMO, have been used to elucidate the information regarding charge transfer within the molecules. Theoretical studies confirmed that in 1 and 2c the trans structures are about 41 and 33 kJ mol(-1) more stable than cis ones. Antibacterial activity and in vitro cytotoxicity of these compounds, as respectively assessed in six bacterial strains and two human tumor cell lines, have been investigated. Results showed the title complexes have the capacity of inhibiting the metabolic growth of bacteria and tumor cells to different extents.

First reported correlation between the calculated gas-phase proton macroaffinities of some metal complexes with their measured formation constants in solution: Zn(II) complexes of a series of tripodal aliphatic tetraamines.

A theoretical study on the first protonation step of a series of metal complexes with the general formula {M(N[(CH2)nNH2][(CH2)mNH2][(CH2)pNH2])2+} (n = m = p = 2, tren; n = 3, m = p = 2, pee; n = m = 3, p = 2, ppe; n = m = p = 3, tpt; n = 2, m = 3, p = 4, epb; and n = m = 3, p = 4, ppb; and M = Zn2+) was reported using both the Hartree-Fock and DFT (B3LYP) levels of theory. For the first time, two kinds of our recently published definitions for gas-phase proton affinities of polybasic ligands, proton microaffinity and proton macroaffinity, were extended to their metal complexes. There is a good correlation between the calculated gas-phase proton macroaffinities and the corresponding formation constants in solution.

Complete gas-phase proton microaffinity analysis of two bulky polyamine molecules.

Density functional theory (DFT) and ab initio (Hartree-Fock) calculations employing the 6-31G* basis set are used to determine gas-phase proton microaffinities (PA(n,i)) of two bulky symmetrical tripodal tetraamine ligands N[(CH2)(4)NH2]3, trbn, and N[(CH2)(5)NH2]3, trpa. The corresponding proton macroaffinities (PA(n)) are calculated not only according to our recently established method but also considering two alternative formulas based on a Boltzmann distribution. The successive protonation macroconstants in aqueous solution for these bulky amines are predicted from the well-defined correlation between the calculated proton macroaffinities, without considering Boltzmann distribution, and the corresponding log Kn for these amines. The overall protonation constants are also predicted by two different methods.