Incoming Ligand Research Articles

Antitumor effects of a tetradentate amido-carboxylate ligands and corresponding square-planar palladium(II) complexes toward some cancer cells. Crystal structure, DFT modeling and ligand to DNA probe Docking simulation

Novel square-planar palladium(II) complexes with O–N–N–O-type ligands H4mda (H4mda=malamido-N,N′-diacetic acid) and H4obp (H4obp=oxamido-N,N′-di-3-propionic acid) were prepared and characterized. The ligands coordinate to the palladium(II) ion via two pairs of deprotonated ligating atoms with square chelation. A four coordinate, square-planar geometry was verified crystallographicaly for the K2[Pd(mda)]⋅H2O complex. The binary and ternary systems of Pd(II) ion with H4mda or H4obp (L) as primary ligands and guanosine (A) as secondary ligand were studied in aqueous solutions in 0.1M NaCl ionic medium at 25°C by potentiometric titrations. In addition, calculations based on density functional methods (DFT) were carried out. A natural bonding orbital analysis indicated that the Pd–N bonds are three-centric in nature and mainly governed by charge transfer via a strong delocalization of the oxygen lone pair with “p” character into the bonding Pd–N orbital. Mononuclear palladium(II) complexes together with amido acid N,O-containing ligands were tested against several tumor cells and reveal significant antitumor activity and lower resistance of tumor cells in vitro than cisplatin. In this paper, interactions of palladium complexes with DNA are discussed in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems. Docking simulation on DNA dodecamer or 29-mer (Lippard solved crystal structures), suggests several favorable interactions with the hydrogen pocket/binding site for the incoming ligands. These results support amidoacids/Pd complexes as novel antitumor drugs and suggest that their potent cell life inhibition may contribute to its anti-cancer efficacy.

Tungsten and molybdenum incomplete cuboidal clusters; kinetico-mechanistic studies and association in dimers

New triangular Mo(IV) and W(IV) incomplete cuboidal cluster complexes containing three η(2)-diethyldithiophosphates (dtp, one per metal centre) and a η(2)(μ)-AcO or η(2)(μ)-dtp ligand bridging two of these centres have been prepared as mono-substituted derivatives and characterized by the usual techniques plus single crystal X-ray diffraction (XRD) analysis in some cases. In the compounds, the single substitutionally available unlocked position is coordinated to different N-donor ligands (1,2-bis(pyridyl)ethylene, pyrimidine, pyrazine) or to the residual solvent. The compounds are very labile and the N-donor ligands are only weakly coordinated, being easily substituted by other donors or coordinating solvents such as acetonitrile. This lability has been explored kinetico-mechanistically by stopped-flow techniques at varying temperatures for the compound [Mo3S4(η(2)-dtp)3(η(2)(μ)-dtp)(H2O)]. By doing so, the nature of the activation process leading to substitution reactions on these complexes has been established as associatively activated and dominated by a very low formation equilibrium constant, that is, by the substitution of the incoming N-donor ligand. Furthermore, the existence of a non-dissociatively activated trigonal 60° fluxional twist has also been established for the η(2)-dtp ligand on the single unlocked position. The lability of the system has also enabled the association in dimers of the acetato derivative, i.e. [Mo3S4(η(2)-dtp)3(η(2)(μ)-AcO)(H2O)], via a pyrazine bridging ligand. After a very careful tuning of the reaction conditions, as established from the kinetico-mechanistic studies, the first single-bridged unsupported dimeric association of {Mo3S4} units, i.e. [{Mo3S4(η(2)-dtp)3(η(2)(μ)-AcO)}2(μ-pyrazine)], has been structurally characterised.

Mechanism of CO Displacement from an Unusually Labile Rhenium Complex: An Experimental and Theoretical Investigation

The displacement of a CO ligand from an unusually labile rhenium carbonyl complex containing a bidentate carboxyaldehyde pyrrolyl ligand by PPh(3) and pyridine has been investigated. The reaction is found to proceed by an associative, preequilibrium mechanism. Theoretical calculations support the experimental data and provide a complete energetic profile for the reaction. While the Re-CO bond is found to be intrinsically weak in these complexes, it is postulated that the unusual lability of this species is due to the presence of a weak aldehyde Re-O link that can easily dissociate to open a coordination site on the metal center and accommodate an incoming ligand prior to CO loss. The resulting intermediate complex has been identified by IR spectroscopy. The presence of the hemilabile pyrrolyl ligand provides a lower-energy reaction channel for the release of CO and may be of relevance in the design of CO-releasing molecules.

Cyanide binding to human plasma heme–hemopexin: A comparative study

Hemopexin (HPX) displays a pivotal role in heme scavenging and delivery to the liver. In turn, heme–Fe–hemopexin (HPX–heme–Fe) displays heme-based spectroscopic and reactivity properties. Here, kinetics and thermodynamics of cyanide binding to ferric and ferrous hexa-coordinate human plasma HPX–heme–Fe (HHPX–heme–Fe(III) and HHPX–heme–Fe(II), respectively), and for the dithionite-mediated reduction of the HHPX–heme–Fe(III)–cyanide complex, at pH 7.4 and 20.0°C, are reported. Values of thermodynamic and kinetic parameters for cyanide binding to HHPX–heme–Fe(III) and HHPX–heme–Fe(II) are K=(4.1±0.4)×10−6M, kon=(6.9±0.5)×101M−1s−1, and koff=2.8×10−4s−1; and H=(6±1)×10−1M, hon=1.2×10−1M−1s−1, and hoff=(7.1±0.8)×10−2s−1, respectively. The value of the rate constant for the dithionite-mediated reduction of the HHPX–heme–Fe(III)–cyanide complex is l=8.9±0.8M−1/2s−1. HHPX–heme–Fe reactivity is modulated by proton acceptor/donor amino acid residue(s) (e.g., His236) assisting the deprotonation and protonation of the incoming and outgoing ligand, respectively.

Structural and Theoretical Basis for Ligand Exchange on Thiolate Monolayer Protected Gold Nanoclusters

Ligand exchange reactions are widely used for imparting new functionality on or integrating nanoparticles into devices. Thiolate-for-thiolate ligand exchange in monolayer protected gold nanoclusters has been used for over a decade; however, a firm structural basis of this reaction has been lacking. Herein, we present the first single-crystal X-ray structure of a partially exchanged Au(102)(p-MBA)(40)(p-BBT)(4) (p-MBA = para-mercaptobenzoic acid, p-BBT = para-bromobenzene thiol) with p-BBT as the incoming ligand. The crystal structure shows that 2 of the 22 symmetry-unique p-MBA ligand sites are partially exchanged to p-BBT under the initial fast kinetics in a 5 min timescale exchange reaction. Each of these ligand-binding sites is bonded to a different solvent-exposed Au atom, suggesting an associative mechanism for the initial ligand exchange. Density functional theory calculations modeling both thiol and thiolate incoming ligands postulate a mechanistic pathway for thiol-based ligand exchange. The discrete modification of a small set of ligand binding sites suggests Au(102)(p-MBA)(44) as a powerful platform for surface chemical engineering.

A survey of place-exchange reaction for the preparation of water-soluble gold nanoparticles

Water-soluble gold nanoparticles (AuNPs) have gained considerable attention because they offer a myriad of potential applications, especially in the fields of biology and medicine. One method to prepare such gold nanoparticles is through the well-known Murray place-exchange reaction. In this method, precursor gold nanoparticles, bearing labile ligands and with very good size distribution, are synthesized first, and then reacted with a large excess of the desired ligand. We report a comparison of the reactivity of several known precursor gold nanoparticles (citrate-stabilized, pentanethiol-stabilized, tetraoctylammonium bromide-stabilized, and 4-dimethylaminopyridine-stabilized) to several biologically relevant ligands, including amino acids, peptides, and carbohydrates. We found that citrate-stabilized and 4-dimethylaminopyridine-stabilized gold nanoparticles have broader reactivities than the other precursors studied. Citrate-stabilized gold nanoparticles are more versatile precursors because they can be prepared in a wide range of sizes and are very stable. The hydrophobic pentane-stabilized gold nanoparticles made them “inert” toward highly water-soluble ligands. Tetraoctylammonium bromide-stabilized gold nanoparticles exhibited selective reactivity, especially for small, unhindered and amphiphilic ligands. Depending on the desired ligand and size of AuNPs, a judicious selection of the available precursors can be made for use in place-exchange reactions. In preparing water-soluble AuNPs with biologically relevant ligands, the nature of the incoming ligand and the size of the AuNP should be taken into account in order to choose the most suitable place-exchange procedure.

Understanding the molecular interactions of different radical scavengers with ribonucleotide reductase M2 (hRRM2) domain: opening the gates and gaining access

We employed a combination of molecular docking and dynamics to understand the interaction of three different radical scavengers (SB-HSC21, ABNM13 and trimidox) with ribonucleotide reductase M2 (hRRM2) domain. On the basis of the observed results, we can propose how these ligands interact with the enzyme, and cease the radical transfer step from the di-iron center to TYR176. All the ligands alter the electron density over TYR176, -OH group by forming an extremely stable H-bond with either -NHOH group, or with phenolic hydroxyl group of the ligands. This change in electronic density disrupts the water bridge between TYR176, -OH and the di-iron center, which stops the single electron transfer process from TYR176, -OH to iron. As a consequence the enzyme is inhibited. Another interesting observation that we are reporting is the two stage gate keeping mechanism of the RR active site tunnel. We describe these as the outer Gate-1 controlled by ARG330, and the inner Gate-2 controlled by SER263, PHE240, and PHE236. We also observed a dynamic conformational shift in these residues, the incoming ligands can go through, and interact with the underlying TYR176, -OH group. From the study we found the active-site of hRRM2 is extremely flexible and shows a significant induced fit.

The formation of an antitubercular complex [Fe(CN)5 (INH)]3− through mercury(II)-catalyzed ligand substitution reaction: A kinetic and mechanistic study

The kinetics and mechanism of the formation of an antitubercular complex [Fe(CN)5(INH)]3− based on the substitution reaction between K4[Fe(CN)6] and isoniazid (INH), i.e., isonicotinohydrazide, catalyzed by Hg2+ in aqueous medium was studied spectrophotometrically at 435 nm (the λmax of the golden-yellow-colored complex [Fe(CN)5(INH)]3−) as a function of pH, ionic strength, temperature, and the concentration of the reactants and the catalyst. The replacement of coordinated CN− in [Fe(CN)6]4− was facilitated by incoming ligand INH under the optimized reaction conditions: pH 3.5 ± 0.02, temperature = 30.0 ± 0.1°C, and ionic strength I = 0.05 M (KNO3). The stoichiometry of the reaction and the stability constant of the complex ([Fe(CN)5(INH)]3−) have been established as 1:1 and 2.10 × 103 M, respectively. The rate of catalyzed reaction was found to be slow at low pH values, to increase with increasing pH, to attain a maximum value at 3.50 ± 0.02, and finally to decrease after pH > 3.5 due to less availability of H+ ions needed to regenerate the catalytic species. The initial rates were evaluated for each variation from the absorbance versus time curves. The reaction was found to be pseudo-first order with respect to [INH] and first order with respect to [Fe(CN)64−] at lower concentration, whereas it was found to be fractional order at higher [INH] and [Fe(CN)64−]. The ionic strength dependence study showed a negative salt effect on the rate of the reaction. Based on experimental results, a mechanism for the studied reaction is proposed. The rate equation derived from this mechanism explains all the experimental observations. The evaluated values of activation parameters for the catalyzed reaction suggest an interchange dissociative (Id) mechanism. © 2012 Wiley Periodicals, Inc. Int J Chem Kinet 44: 398–406, 2012

Functional Dynamics of Proteins

Functional Dynamics of Proteins

Nucleation and Island Growth of Alkanethiolate Ligand Domains on Gold Nanoparticles

The metal oxide cluster α-AlW(11)O(39)(9-) (1), readily imaged by cryogenic transmission electron microscopy (cryo-TEM), is used as a diagnostic protecting anion to investigate the self-assembly of alkanethiolate monolayers on electrostatically stabilized gold nanoparticles in water. Monolayers of 1 on 13.8 ± 0.9 nm diameter gold nanoparticles are displaced from the gold surface by mercaptoundecacarboxylate, HS(CH(2))(10)CO(2)(-) (11-MU). During this process, no aggregation is observed by UV-vis spectroscopy, and the intermediate ligand-shell organizations of 1 in cryo-TEM images indicate the presence of growing hydrophobic domains, or "islands", of alkanethiolates. UV-vis spectroscopic "titrations", based on changes in the surface plasmon resonance upon exchange of 1 by thiol, reveal that the 330 ± 30 molecules of 1 initially present on each gold nanoparticle are eventually replaced by 2800 ± 30 molecules of 11-MU. UV-vis kinetic data for 11-MU-monolayer formation reveal a slow phase, followed by rapid self-assembly. The Johnson, Mehl, Avrami, and Kolmogorov model gives an Avrami parameter of 2.9, indicating continuous nucleation and two-dimensional island growth. During nucleation, incoming 11-MU ligands irreversibly displace 1 from the Au-NP surface via an associative mechanism, with k(nucleation) = (6.1 ± 0.4) × 10(2) M(-1) s(-1), and 19 ± 8 nuclei, each comprised of ca. 8 alkanethiolates, appear on the gold-nanoparticle surface before rapid growth becomes kinetically dominant. Island growth is also first-order in [11-MU], and its larger rate constant, k(growth), (2.3 ± 0.2) × 10(4) M(-1) s(-1), is consistent with destabilization of molecules of 1 at the boundaries between the hydrophobic (alkanethiolate) and the electrostatically stabilized (inorganic) domains.

Aging of Gold Nanoparticles: Ligand Exchange with Disulfides

Aging of thiolate protected gold nanoparticles (AuNPs) results in reduced reactivity in the disulfide exchange as monitored by electron paramagnetic resonance (EPR) spectroscopy with a bisnitroxide disulfide incoming ligand. Factors determining the reactivity of the aged particles were investigated. The presence of different binding sites on the surface of AuNPs and a surface reorganization process during aging can explain observed reactivity trends.

Theory and simulation of diffusion-influenced, stochastically gated ligand binding to buried sites.

We consider the diffusion-influenced rate coefficient of ligand binding to a site located in a deep pocket on a protein; the binding pocket is flexible and can reorganize in response to ligand entrance. We extend to this flexible protein-ligand system a formalism developed previously [A. M. Berezhkovskii, A, Szabo, and H.-X. Zhou, J. Chem. Phys. 135, 075103 (2011)] for breaking the ligand-binding problem into an exterior problem and an interior problem. Conformational fluctuations of a bottleneck or a lid and the binding site are modeled as stochastic gating. We present analytical and Brownian dynamics simulation results for the case of a cylindrical pocket containing a binding site at the bottom. Induced switch, whereby the conformation of the protein adapts to the incoming ligand, leads to considerable rate enhancement.

Competitive ligand/chelate binding in [Cu(TMPA)] + and [Cu(tren)] + based complexes

The competition between coordination of an incoming ligand (CO, CH 3CN, PH 3, H 2O, MeOH, PhOH and O 2 in its triplet state) and decoordination of one arm of the tripod is examined in the case of the [Cu(TMPA)] + and [Cu(tren)] + complexes from a theoretical point of view. It is shown that in the case of strong ligand (CO, CH 3CN and PH 3), arm and ligand coordination are competitive but that coordination of both is the most favored structure. In the case of ROH ligands, a structure with one arm decoordinated and interacting through H-bond with the hydroxyl hydrogen is found. This structure is of special interest as it allows liberation of one bonding site, which can be used for further dioxygen coordination. The consequences of these results on the oxidation of alcohols by dioxygen catalyzed by these classes of complexes are discussed.

Mechanism and Kinetics of Ligand Exchange between Ferric Citrate and Desferrioxamine B

The kinetics of ligand exchange between ferric citrate and desferrioxamine B (DFB) was investigated at pH 8.0 and high citrate/Fe molar ratios (500-5000) with particular attention given to understanding the precise mechanism of ligand exchange. Ferric citrate complexes present in a test solution and therefore involved in the reaction with the incoming ligand (DFB) were initially examined by evaluating ferric citrate speciation on the basis of published thermodynamic constants. The speciation analysis indicated that mononuclear (mono- and dicitrate) ferric complexes are the major species responsible for the ligand exchange with DFB under the conditions examined in the present work. Given the tendency of DFB to adjunctively associate with the ferric citrate complexes, we propose a kinetic model containing the following three mechanisms: (i) direct association of DFB to the ferric dicitrate complex prior to any dissociation of citrate molecules from the Fe center, (ii) adjunctive association of DFB toward ferric monocitrate complex following dissociation of one molecule of citrate from the parent complex, and (iii) complexation of hydrated Fe by DFB after sequential dissociation of two molecules of citrate from the Fe center. Overall rates for the ligand exchange were determined by spectrophotometrically monitoring the formation of ferrioxamine B. Further analysis in quantifying the rate of each mechanism by use of published and determined rate constants of relevant elemental reactions suggested that the first and second mechanisms were significant under our experimental conditions where [Cit] ≫ [DFB] with the relative importance of these two pathways depending on citrate concentration.

Kinetics and Mechanism of the Ligand Substitution Reaction of the Di-μ-hydroxobis(bipyridyl)dipalladium(II) Ion with some Bio-relevant Ligands

The interaction of di-μ-hydroxobis(bipyridyl)dipalladium(II) with the selected bio-relevant ligands: thioglycolic acid (HL1), glutathione(HL2) and DL-penicillamine(HL3) has been studied spectrophotometrically in aqueous medium as a function of complex and ligand concentrations, pH, and temperature at constant ionic strength. Two consecutive reaction steps are observed: the first step is dependent on the incoming ligand concentration and the second step which is independent, is assigned to ring closure. The activation parameters, conductivity data and IR data obtained also support the proposed mechanism.

Theoretical study on the interaction of titanocene dichloride with deoxyguanosine monophosphate

The completely hydrolyzed titanocene dichloride, [Cp 2Ti(H 2O) 2] 2+ binding to guanine (G) and phosphate group sites of DNA were investigated by DFT method, with using deoxyguanosine monophosphate (dGMP) as incoming ligand. In the first substitutions, the calculations reveal that the diaquated titanocene binding to O6 shows the lowest activation free energy with 17.9 kcal/mol, closely followed by N7 is 20.5 kcal/mol and the O of phosphate group is 26.3 kcal/mol, respectively. It was also found that all the titanation processes are mildly endothermic. In addition, for the Ti–B(dGMP) in all separated products, the bond dissociation free energies (BDFE) of Ti–O(P, P = phosphate) is higher than those of Ti–N7/O6. In the second substitutions, the reactions leading to the didentate adducts are considered. For bidentate-bridging N7, O6 binding mode, the path of the metal Ti binding to O6 has the lower activation free energy (11.3 kcal/mol) than that of the metal Ti binding to N7 (15.3 kcal/mol). For the bidentate-bridging N7, O(P) binding mode, the path of the metal Ti binding to O(P) has the lower activation free energies (25.3 kcal/mol) than that of the metal Ti binding to N7 (26.2 kcal/mol).

Synthesis and Reactivity of [(PhB(CH2PPh2)3-κ3P)Ru(NCMe)3]PF6 and Its Potential as a Transfer Hydrogenation Catalyst

The acetonitrile ligands in [(PhB(CH2PPh2)3-κ3P)Ru(NCMe)3]PF6 (1) (which contains a facially coordinated anionic tripodal phosphine ligand) are labile and are rapidly replaced by other ligands, although the steric profile of the phosphine ligand limits the size and the number of the incoming ligands. Complex 1 and some of its derivatives proved to be very efficient and rapid transfer hydrogenation precatalysts and yielded turnover frequencies (TOFs) greater than those typically observed for most other ruthenium-based catalysts.

Kinetic and thermodynamic studies on reactions of [PtCl(bpma)]+ and [Pt(bpma)H2O]2+ (bpma = bis-(2-pyridylmethyl)amine) with some azoles and diazines

Substitution reactions of the complexes [Pt(bpma)H2O]2+ and [PtCl(bpma)]+, where bpma is bis-(2-pyridylmethyl)amine, with the nitrogen-donor ligands 1,2,4-triazole, pyrazole and pyridazine were studied in aqueous 0.1 M NaClO4 using variable-temperature UV–VIS spectrophotometry. The reactions of the aqua complex were studied at pH 2.5, and those of the chloro complex were studied in the presence of 10 mM NaCl to prevent their hydrolysis. The values obtained for the second-order rate constants indicate that the complexes with bpma are more reactive than those with diethylenetriamine. In both cases, the aqua complexes are more reactive than the corresponding chloro complexes. The reactivity of the incoming ligands follows the order: 1,2,4-triazole > pyridazine > pyrazole. Activation parameters were determined for all the reactions, and the negative entropies of activation (∆S≠) support an A or Ia mechanism.

Formation of the Distinct Redox‐Interrelated Forms of Nitric Oxide from Reaction of Dinitrosyl Iron Complexes (DNICs) and Substitution Ligands

Release of the distinct NO redox-interrelated forms (NO(+), *NO, and HNO/NO(-)), derived from reaction of the dinitrosyl iron complex (DNIC) [(NO)(2)Fe(C(12)H(8)N)(2)](-) (1) (C(12)H(8)N=carbazolate) and the substitution ligands (S(2)CNMe(2))(2), [SC(6)H(4)-o-NHC(O)(C(5)H(4)N)](2) ((PyPepS)(2)), and P(C(6)H(3)-3-SiMe(3)-2-SH)(3) ([P(SH)(3)]), respectively, was demonstrated. In contrast to the reaction of (PyPepS)(2) and DNIC 1 in a 1:1 stoichiometry that induces the release of an NO radical and the formation of complex [PPN][Fe(PyPepS)(2)] (4), the incoming substitution ligand (S(2)CNMe(2))(2) triggered the transformation of DNIC 1 into complex [(NO)Fe(S(2)CNMe(2))(2)] (2) along with N-nitrosocarbazole (3). The subsequent nitrosation of N-acetylpenicillamine (NAP) by N-nitrosocarbazole (3) to produce S-nitroso-N-acetylpenicillamine (SNAP) may signify the possible formation pathway of S-nitrosothiols from DNICs by means of transnitrosation of N-nitrosamines. Protonation of DNIC 1 by [P(SH)(3)] triggers the release of HNO and the generation of complex [PPN][Fe(NO)P(C(6)H(3)-3-SiMe(3)-2-S)(3)] (5). In a similar fashion, the nucleophilic attack of the chelating ligand P(C(6)H(3)-3-SiMe(3)-2-SNa)(3) ([P(SNa)(3)]) on DNIC 1 resulted in the direct release of [NO](-) captured by [((15)NO)Fe(SPh)(3)](-), thus leading to [((15)NO)((14)NO)Fe(SPh)(2)](-). These results illustrate one aspect of how the incoming substitution ligands ((S(2)CNMe(2))(2) vs. (PyPepS)(2) vs. [P(SH)(3)]/[P(SNa)(3)]) in cooperation with the carbazolate-coordinated ligands of DNIC 1 function to control the release of NO(+), *NO, or [NO](-) from DNIC 1 upon reaction of complex 1 and the substitution ligands. Also, these results signify that DNICs may act as an intermediary of NO in the redox signaling processes by providing the distinct redox-interrelated forms of NO to interact with different NO-responsive targets in biological systems.

Rapid functionalization of metal nanoparticles by moderator-tunable ligand-exchange process for biosensor designs

A new method for rapid functionalization of metal nanoparticles based on a moderator-tunable 2D nucleation and growth of ligand-exchange domains has been developed for the design of biosensors with nanoparticle-enhanced sensory films and other applications. The proposed functionalization of gold nanoparticles proceeds through the nucleation and avalanche growth of ligand-exchange domains in the self-assembled monolayer film on a gold nanoparticle surface. The nucleation and growth is controllable by a moderator molecule. The experimental system described presents a ligand-exchange process at citrate-capped gold nanoparticles, with homocysteine acting as the incoming ligand and glutathione as the moderator. The kinetics of the nucleation and growth driven ligand-exchange is characterized by a sigmoidal switching function and differs from that of the usually observed Langmuirian pseudo-first-order process corresponding to the random place-exchange. The ultra-fast functionalization process was monitored using resonance elastic light scattering (RELS) spectroscopy and confirmed by UV–vis plasmonic band absorbance measurements.