Kinetics Of Substitution Research Articles

Substitution Kinetics, Albumin and Transferrin Affinities, and Hypoxia All Affect the Biological Activities of Anticancer Vanadium(V) Complexes.

Limited stability of most transition-metal complexes in biological media has hampered their medicinal applications but also created a potential for novel cancer treatments, such as intratumoral injections of cytotoxic but short-lived anticancer drugs. Two related V(V) complexes, [VO(Hshed)(dtb)] (1) and [VO(Hshed)(cat)] (2), where H2shed = N-(salicylideneaminato)-N'-(2-hydroxyethyl)-1,2-ethanediamine, H2dtb = 3,5-di-tert-butylcatechol, and H2cat = 1,2-catechol, decomposed within minutes in cell culture medium at 310 K (t1/2 = 43 and 9 s for 1 and 2, respectively). Despite this, both complexes showed high antiproliferative activities in triple-negative human breast cancer (MDA-MB-231) cells, but the mechanisms of their activities were radically different. Complex 1 formed noncovalent adducts with human serum albumin, rapidly entered cells via passive diffusion, and was nearly as active in a short-term treatment (IC50 = 1.9 ± 0.2 μM at 30 min) compared with a long-term treatment (IC50 = 1.3 ± 0.2 μM at 72 h). The activity of 1 decreased about 20-fold after its decomposition in cell culture medium for 30 min at 310 K. Complex 2 showed similar activities (IC50 ≈ 12 μM at 72 h) in both fresh and decomposed solutions and was inactive in a short-term treatment. The activity of 2 was mainly due to the reactions among V(V) decomposition products, free catechol, and O2 in cell culture medium. As a result, the activity of 1 was less sensitive than that of 2 to the effects of hypoxic conditions that are characteristic of solid tumors and to the presence of apo-transferrin that acts as a scavenger of V(V/IV) decomposition products in blood serum. In summary, complex 1, but not 2, is a suitable candidate for further development as an anticancer drug delivered via intratumoral injections. These results demonstrate the importance of fine-tuning the ligand properties for the optimization of biological activities of metal complexes.

Impact of Alkyl Core Substitution Kinetics in Diaryl Dihydrophenazine Photoredox Catalysts on Properties and Performance in O-ATRP.

Organocatalyzed atom transfer radical polymerization (O-ATRP) is a controlled radical polymerization method mediated by organic photoredox catalysts (PCs) for producing polymers with well-defined structures. While N,N-diaryl dihydrophenazine PCs have successfully produced polymers with low dispersity (Đ < 1.3) in O-ATRP, low initiator efficiencies (I* ~ 60-80%) indicate an inability to achieve targeted molecular weights and have been attributed to the addition of radicals to the PC core. In this work, we measure the rates of alkyl core substitution (AkCS) to gain insight into why PCs differing in N-aryl group connectivity exhibit differences in polymerization control. Additionally, we evaluate how PC properties evolve during O-ATRP when a non-core-substituted PC is used. PC 1 with 1-naphthyl groups in the N-aryl position resulted in faster AkCS (k 1 = 1.21 ± 0.16 × 10-3 s-1, k 2 = 2.04 ± 0.11 × 10-3 s-1) and better polymerization control at early reaction times as indicated by plots of molecular weight (number average molecular weight = M n) vs conversion compared to PC 2 with 2-naphthyl groups (k 1 = 6.28 ± 0.38 × 10-4 s-1, k 2 = 1.15 ± 0.07 × 10-3 s-1). The differences in rates indicate that N-aryl connectivity can influence polymerization control by changing the rate of AkCS PC formation. The rate of AkCS increased from the initial to the second substitution, suggesting that PC properties are modified by AkCS. Increased PC radical cation (PC•+) oxidation potentials (E 1/2 = 0.26-0.27 V vs SCE) or longer triplet excited-state lifetimes (τ T1 = 1.4-33 μs) for AkCS PCs 1b and 2b compared to parent PCs 1 and 2 (E 1/2 = 0.21-0.22 V vs SCE, τ T1 = 0.61-3.3 μs) were observed and may explain changes to PC performance with AkCS. Insight from evaluation of the formation, properties, and performance of AkCS PCs will facilitate their use in O-ATRP and in other PC-driven organic transformations.

Biomolecular interactions of 1,3-bis(2-arylimino)isoindolate-based palladium(II) complexes: Substitution kinetics, DNA/protein-binding, and molecular docking approaches

A series of 1,3-bis(2-arylimino)isoindoline Pd(II) complexes core viz.; Chlorido(1,3-bis(2-pyridylimino)isoindoline)palladium(II), Pd1, Chlorido(1,3-bis(4-methyl-2-pyridylimino)isoindoline)palladium(II), Pd2, Chlorido(1,3-bis(2-pyridylimino)benz(f)isoindoline)palladium(II), Pd3 and Chlorido(1,3-Bis(1-isoquinolylimino)isoindoline)palladium(II), Pd4 were synthesized, appropriately characterized and the crystal structure of Pd2 elucidated. The kinetics and mechanism of the substitution of the chloride ligand with thiourea ligands, Tu, Dmtu and Tmtu, from the complexes were investigated under pseudo-first-order conditions. The analyses were performed using stopped-flow analyzer or UV–visible spectrophotometer. The reactions proceeded through two consecutive steps for most complexes with exception of Pd4 showing only a single step. The substitution rates followed the order: Pd1>Pd2>Pd3>Pd4 due to varying degrees of steric influences and σ-/π-donations caused by the methylation and benzannulation on the cis-/trans-positions of the pyridyl rings of the BPI. The quenching of the fluorescence of CT-DNA/EB by the Pd(II) complexes suggests static quenching mechanism. The simulated docking of the complexes onto CT-DNA suggests they bind mainly in the minor grooves of DNA. The UV–Visible absorption titrations and quenching of tryptophan (Trp) fluorescence of BSA by the complexes depict reasonable interactions which occur mainly in the hydrophobic domains of the former. The order of strength of the interaction of the complexes with DNA or BSA is consistent with the rates of substitution kinetics.

Interzeolite Transformation of Borosilicate MWW to Metallosilicate BEA-Type Zeolites: Separated Kinetics of Structural Transformation and Metal Substitution

The synthesis of cobalt-, nickel-, and zincosilicate β zeolites (Co-BEA, Ni-BEA, and Zn-BEA, respectively) via a single-step hydrothermal interzeolite transformation of borosilicate MWW (B-MWW) with each metal precursor solution was systematically investigated. While all three metallosilicates exhibited distinct BEA structures with stable framework metal species, their structural transformation and metal substitution kinetics differed depending on the type of metal. The crystallization of Co-BEA and Ni-BEA was completed within two days, while that of Zn-BEA continued even after seven days. Apart from the crystallization kinetics, the incorporation rate of Co into the framework of the BEA structure was slower than that of the other two metals. The characteristics of the BEA structure according to the type of framework heteroatom were further demonstrated using density functional theory calculations. Despite having a comparable metal content (ca. 3 wt %), the Lewis acidities of fully crystallized Co-, Ni-, and Zn-BEA were different corresponding to the types of framework metals. These three metallosilicates showed good catalytic activity for Lewis acid-catalyzed glucose conversion, and the catalytic results were attributed to the intrinsic properties of the catalysts determined from their synthesis stage.

Electronic and ring size effects of N-heterocyclic carbenes on the kinetics of ligand substitution reactions and DNA/protein interactions of their palladium(II) complexes

The synthesis, substitution kinetics and DNA/BSA interactions of four cationic Pd(II) complexes [Pd(1)Cl]BF4 (Pd1), [Pd(2)Cl]BF4 (Pd2), [Pd(3)Cl]BF4 (Pd3) and [Pd(4)Cl]BF4 (Pd4), derived from the reaction of [PdCl2(NCCH3)2] with ligands 2,6-bis(3-methylimidazolium-1-yl)pyridine dibromide (1), 2,6-bis(3-ethylimidazolium-1-yl)pyridine dibromide (2), 2,6-bis(1-methylimidazole-2-thione)pyridine (3), and 2,6-bis(1-ethylimidazole-2-thione)pyridine (4), respectively are reported. The complexes were characterised by various spectroscopic techniques and single crystal X-ray diffraction for compound Pd2. Kinetic reactivity of the complexes with the biologically relevant nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-monophosphate sodium salt (5’-GMP) was in the order: Pd1 > Pd2 > Pd3 > Pd4, which was largely dependent on the electronic and ring size of the chelate ligands, consistent with Density functional theory (DFT) simulations. The interactions of the complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) binding titrations showed strong binding. Both the experimental and in silico data reveal CT-DNA intercalative binding mode.Graphical abstract

Dinuclear nitrido-bridged osmium complexes inhibit the mitochondrial calcium uniporter and protect cortical neurons against lethal oxygen-glucose deprivation.

Dysregulation of mitochondrial calcium uptake mediated by the mitochondrial calcium uniporter (MCU) is implicated in several pathophysiological conditions. Dinuclear ruthenium complexes are effective inhibitors of the MCU and have been leveraged as both tools to study mitochondrial calcium dynamics and potential therapeutic agents. In this study, we report the synthesis and characterization of Os245 ([Os2(μ-N)(NH3)8Cl2]3+) which is the osmium-containing analogue of our previously reported ruthenium-based inhibitor Ru265. This complex and its aqua-capped analogue Os245' ([Os2(μ-N)(NH3)8(OH2)2]5+) are both effective inhibitors of the MCU in permeabilized and intact cells. In comparison to the ruthenium-based inhibitor Ru265 (k obs = 4.92 × 10-3 s-1), the axial ligand exchange kinetics of Os245 are two orders of magnitude slower (k obs = 1.63 × 10-5 s-1) at 37 °C. The MCU-inhibitory properties of Os245 and Os245' are different (Os245 IC50 for MCU inhibition = 103 nM; Os245' IC50 for MCU inhibition = 2.3 nM), indicating that the axial ligands play an important role in their interactions with this channel. We further show that inhibition of the MCU by these complexes protects primary cortical neurons against lethal oxygen-glucose deprivation. When administered in vivo to mice (10 mg kg-1), Os245 and Os245' induce seizure-like behaviors in a manner similar to the ruthenium-based inhibitors. However, the onset of these seizures is delayed, a possible consequence of the slower ligand substitution kinetics for these osmium complexes. These findings support previous studies that demonstrate inhibition of the MCU is a promising therapeutic strategy for the treatment of ischemic stroke, but also highlight the need for improved drug delivery strategies to mitigate the pro-convulsant effects of this class of complexes before they can be implemented as therapeutic agents. Furthermore, the slower ligand substitution kinetics of the osmium analogues may afford new strategies for the development and modification of this class of MCU inhibitors.

Distal scaffold flexibility accelerates ligand substitution kinetics in manganese(I) tricarbonyls: flexible thianthrene versus rigid anthracene scaffolds.

This work investigates the effect of molecular flexibility on fundamental ligand substitution kinetics in a pair of manganese(I) carbonyls supported by scaffold-based ligands. In previous work, we reported that the planar and rigid, anthracene-based scaffold with two pyridine 'arms' (Anth-py2, 2) serves as a bidentate, cis donor set, akin to a strained bipyridine (bpy). In the present work, we have installed a more flexible and dynamic scaffold in the form of thianthrene (Thianth-py2, 1), wherein the scaffold in the free ligand exhibits a ∼130° dihedral angle in the solid state. Thianth-py2 also exhibits greater flexibility (molecular motion) in solution compared with Anth-py2, as evidenced by longer 1H NMR T1 times Thianthy-py2 (T1 = 2.97 s) versusAnth-py2 (T1 = 1.91 s). Despite the exchange of rigid Anth-py2 for flexible Thianth-py2 in the complexes [(Anth-py2)Mn(CO)3Br] (4) and [(Thianth-py2)Mn(CO)3Br] (3), respectively, nearly identical electronic structures and electron densities were observed at the Mn center: the IR of 3 exhibits features at 2026, 1938 and 1900 cm-1, nearly identical to the features of the anthracene-based congener (4) at 2027, 1936 and 1888 cm-1. Most importantly, we assessed the effect of ligand-scaffold flexibility on reactivity and measured the rates of an elementary ligand substitution reaction. For ease of IR study, the corresponding halide-abstracted, nitrile-bound (PhCN) cations [(Thianth-py2)Mn(CO)3(PhCN)](BF4) (6) and [(Anth-py2)Mn(CO)3(PhCN)](BF4) (8) were generated in situ, and the PhCN → Br- back-reaction was monitored. The more flexible 3 (thianth-based) exhibited ∼3-4× faster ligand substitution kinetics (k25 C = 22 × 10-2 min-1, k0 C = 43 × 10-3 min-1) than the rigid analogue 4 (anth-based: (k25 C = 6.0 × 10-2 min-1, k0 C = 9.0 × 10-3 min-1) on all counts. Constrained angle DFT calculations revealed that despite large changes in the thianthrene scaffold dihedral angle, the bond metrics of 3 about the metal center remain unchanged; i.e. the 'flapping' motion is strictly a second coordination sphere effect. These results suggest that the local environment of molecular flexibility plays a key role in determining reactivity at the metal center, which has essential implications for understanding the reactivity of organometallic catalysts and metalloenzyme active sites. We propose that this molecular flexibility component of reactivity can be considered a thematic 'third coordination sphere' that dictates metal structure and function.

Synthesis, characterization and in vitro cytotoxicity of ruthenium(II) metronidazole complexes: Cell cycle arrest at G1/S transition and apoptosis induction in MCF-7 cells

Ruthenium compounds are known to be potential drug candidates since they offer the potential for reduced toxicity. Furthermore, the various oxidation states, different mechanisms of action and ligand substitution kinetics give them advantages over platinum-based complexes, making them suitable for use in biological applications. So, herein, novel ruthenium(II) complexes with metronidazole as ligand were obtained [RuCl(MTNZ)(dppb)(4,4′-Mebipy)]PF6 (1), [RuCl(MTNZ)(dppb)(4,4′-Methoxybipy)]PF6 (2), [RuCl(MTNZ)(dppb)(bipy)]PF6 (3) and [RuCl(MTNZ)(dppb)(phen)]PF6 (4) where, MTNZ = metronidazole, dppb = 1,4-bis(diphenylphosphino)butane, 4,4′-Mebipy = 4,4′-dimethyl-2,2′-bipyridine, 4,4′-Methoxybipy = 4,4′-dimethoxy-2,2′-bipyridine, bipy = 2,2′-bipyridine and phen = 1,10-phenanthroline. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV–Vis spectroscopy, cyclic voltammetry, 31P{1H}, 1H, 13C{1H} and Dept 135 NMR and mass spectrometry. The interaction of complexes 1–4 with DNA was evaluated, and their cytotoxicity profiles were determined on four different tumor cell lines derived from human cancers (SK-MEL-147, melanoma; HepG2, hepatocarcinoma; MCF-7, estrogen-positive breast cancer; A549, non-small cell lung cancer). We demonstrated that complexes (1) and (3) are promising antitumor agents once inhibited the proliferative behavior of MCF-7 cells and induced apoptosis.

Synthesis, substitution kinetics, DNA/BSA binding and cytotoxicity of tridentate N^E^N (E = NH, O, S) pyrazolyl palladium(II) complexes.

The pincer complexes, [Pd(L1)Cl]BF4 (PdL1), [Pd(L2)Cl]BF4 (PdL2), [Pd(L3)Cl]BF4 (PdL3), [Pd(L4)Cl]BF4 (PdL4) were prepared by reacting the corresponding ligands, 2,6-bis[(1H-pyrazol-1-yl)methyl]pyridine (L1), bis[2-(1H-pyrazol-1-yl)ethyl]amine (L2), bis[2-(1H-pyrazol-1-yl)ethyl]ether (L3), and bis[2-(1H-prazol-1-yl)ethyl]sulphide (L4) with [PdCl2(NCMe)]2 in the presence NaBF4. The solid-state structures of complexesPdL1-PdL4 confirmed a tridentate coordination mode, with one chloro ligand completing the coordination sphere to afford square-planar complexes. Chemical behaviour of the complexes in solution confirms their stability in both aqueous and DMSO stock media. The electrochemical properties of the compounds showed irreversible two-electron reduction process. Kinetic reactivity of Pd complexes with the biological nucleophiles viz, thiourea (Tu), L-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5'-GMP) followed the order: PdL2 < PdL3 < PdL4, and PdL2 < PdL1. The kinetic reactivity is subject to the electronic effects of the spectator ligand(s), and the trend was supported by the DFT computed results. The palladium complexes PdL1-PdL4 bind to calf thymus (CT-DNA) via intercalation mode. In addition, the bovine serum albumin (BSA) showed good binding affinity to the complexes. The mode of quenching mechanism of the intrinsic fluorescence of CT-DNA and BSA by the complexes was found to be static. The order of interactions of the complexes with DNA and BSA was in tandem with the rate of substitution kinetics. The complexes, however, displayed relatively low cytotoxicity (IC50 > 100µM) when tested against the human cervical adenocarcinoma (HeLa) cell line and the transformed human lung fibroblast cell line (MRC-5 SV2).

Kinetics of Nucleophilic Substitution of Compounds Containing Multiple Leaving Groups Bound to a Neopentyl Skeleton.

Ammonium salt derivatives with a neopentyl moiety are remarkably stable against Hofmann elimination, but the neopentyl moiety slows nucleophilic substitution, complicating their synthesis. To identify the best leaving group for the synthesis of the ammonium salts, we prepared six 1,1,1-tris(X-methyl)ethane derivatives, where X is chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate (triflate), and studied the kinetics of their reactions with sodium, cesium, or tetramethylammonium azide in deuterated dimethylsulfoxide (DMSO) at 100 °C by NMR spectroscopy. Iodide and bromide were found to be more reactive than p-toluenesulfonate and methanesulfonate. As expected, the best leaving group for nucleophilic substitution was triflate. Despite the usual high reactivity and instability of primary alkyl triflates, neopentyl triflate can be used as a stable but sufficiently reactive reactant for nucleophilic substitution on neopentyl skeletons.

Complex structures, formation thermodynamics and substitution reaction kinetics in the copper(II) – glycylglycylglycine – l/d/dl-histidine system

Complex formation thermodynamics in the copper(II) – glycylglycylglycine (GGG·H) and copper(II) – glycylglycylglycine – l/d-histidine (HisH) systems (25.0 °C, 1.0 M KNO3) was investigated by pH-potentiometric titration and spectrophotometry methods in a wide pH range (2–13). Five hetero-ligand complexes were identified, three of which were characterized for the first time including one binuclear complex. Parameters of individual absorption spectra and ESR spectra of the heteroligand copper(II) complexes with glycylglycylglycine and histidine were obtained for the first time. Complex structures were optimized by DFT computations on the CAM-B3LYP/TZVPP and PBE/TZVPP levels with accounting solvent effect by the C-PCM model. For the complex Cu(GGG·H-2)(His)2− the rapid exchange between two isomers with axial coordination of the imidazole or carboxyl group of His− was first found. It was shown that the complex Cu2(GGG·H-2)(His)(HisH-1)2− presents as two isomers where deprotonated imidazole of the HisH-12− ligand connects two copper ions. The kinetics of glycylglycylglycine substitution by l/dl-histidine was investigated by stopped-flow technique with spectrophotometric detection and three-step scheme of the investigated process was proposed. An unusual stereoselective effect in the tripeptide substitution by anionic form of histidine was revealed and interpreted on the basis of the formation of heteroligand complexes as intermediates in overall processes, that was confirmed by DFT calculations. It is emphasized that only combination of several informative methods (pH-metry, UV–Vis-spectroscopy, ESR, stopped-flow, and DFT calculations) made it possible to reliably describe simultaneously the thermodynamics of formation, the kinetics of substitution reactions, and the structure of complexes in the complex ternary system under study.

Role of π-conjugation on the coordination behaviour, substitution kinetics, DNA/BSA interactions, and in vitro cytotoxicity of carboxamide palladium(II) complexes.

Treatments of N-(pyridin-2-ylmethyl)pyrazine-2-carboxamide (L1), N-(quinolin-8-yl)pyrazine-2-carboxamide (L2), N-(quinolin-8-yl)picolinamide (L3) and N-(quinolin-8-yl)quinoline-2-carboxamide (L4) with [PdCl2(NCMe)]2 afforded the corresponding Pd(ii) complexes, [Pd(L1)Cl] (PdL1); [Pd(L2)Cl] (PdL2); [Pd(L3)Cl] (PdL3); and [Pd(L4)Cl] (PdL4) in moderate yields. Structural characterisation of the compounds was achieved by NMR and FT-IR spectroscopies, elemental analyses and single crystal X-ray crystallography. The solid-state structures of complexes PdL2-PdL4 established the presence of one tridentate carboxamide and Cl ligands around the Pd(ii) coordination sphere, to give distorted square planar complexes. Electrochemical investigations of PdL1-PdL4 showed irreversible one-electron oxidation reactions. Kinetics reactivity of the complexes towards bio-molecules, thiourea (Tu), l-methionine (L-Met) and guanosine 5'-diphosphate disodium salt (5'-GMP) decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, in tandem with the density functional theory (DFT) data. The complexes bind favourably to calf thymus (CT-DNA), and bovine serum albumin (BSA), and the order of their interactions agrees with the substitution kinetics trends. The in vitro cytotoxic activities of PdL1-PdL4 were examined in cancer cell lines A549, PC-3, HT-29, Caco-2, and HeLa, and a normal cell line, KMST-6. Overall, PdL1 and PdL3 displayed potent cytotoxic effects on A549, PC-3 HT-29 and Caco-2 comparable to cisplatin. All the investigated complexes exhibited lower toxicity on normal cells than cisplatin.

The influence of α,α′-diimine bridging ligand on the reactivity of binuclear para-cymene ruthenium(II) complexes. Kinetic, mechanistic and computational study

Substitution kinetics of the aqua ligands in four binuclear ruthenium(II) para-cymene complexes with different α,α′-diimine bridging ligands [2-pyridylaldazine (Ru-1), p-phenylenebis(picoline)aldimine (Ru-2), p-biphenylenebis(picoline)aldimine (Ru-3) and p-xylenebis(picoline)aldimine (Ru-4)] was investigated as a function of nucleophile concentration and temperature under pseudo-first order conditions using thiourea nucleophiles. The rates of the simultaneous substitution of the aqua ligands decreased in the order: Ru-1 > Ru-4 > Ru-3 > Ru-2. The reactivity of the complexes is controlled by the inherent electronic and steric contributions of the bridging ligand. The strong π-acceptor bridging ligand is responsible for the high reactivity observed in Ru-1 compared to the rest of the complexes. From Ru-2 to Ru-4, the reactivity increases with decrease in steric congestion around the metal centres. The cage effect plays a role in the enhanced reactivity of Ru-4 compared to Ru-3 and Ru-2. Reactivity trends are excellently supported by computational results. All the complexes showed a stepwise deprotonation of the coordinated aqua ligands except Ru-4 and the pKa values increased from Ru-1 to Ru-4 due to progressive increase in σ-donicity of the spacers. The activation parameters (ΔH≠>0, ΔS≠<0) obtained for all the complexes support an associative mechanism of activation.

Palladium(II) complexes of tridentate bis(benzazole) ligands: Structural, substitution kinetics, DNA interactions and cytotoxicity studies

Reactions of 2,6-bis(benzimidazol-2-yl)pyridine (L1), 2,6-bis(benzoxazol-2-yl)pyridine (L2), and 2,6-bis(benzothiazol-2-yl)pyridine (L3) with [Pd(NCMe)2Cl2] in the presence of NaBF4 afforded the corresponding Pd(II) complexes, [Pd(L1)Cl]BF4, PdL1; [Pd(L2)Cl]BF4, PdL2; [Pd(L3)Cl]BF4, PdL3; respectively, while reaction of bis[(1H-benzimidazol-2-yl)methyl]amine (L4) with [Pd(NCMe)2Cl2] afforded complex [Pd(L4)Cl]Cl, PdL4. Characterisation of the complexes was accomplished using NMR, IR, MS, elemental analyses and single crystal X-ray crystallography. Ligand substitution kinetics of these complexes by biological nucleophiles thiourea (Tu), L-methionine (L-Met) and guanosine 5′-diphosphate disodium salt (5-GMP) were examined under pseudo-first order conditions. The reactivity of the complexes decreased in the order: PdL1 > PdL2 > PdL3 > PdL4, ascribed to electronic effects. Density functional theory (DFT) supported this trend. Studies of interaction of the Pd(II) complexes with calf thymus DNA (CT-DNA) revealed strong binding affinities via intercalative binding mode. Molecular docking studies established associative non-covalent interactions between the Pd complexes and DNA. The in vitro cytotoxic activities of PdL1–PdL4 were assessed in cancer cell lines HeLa and MRC5-SV2 and a normal cell line MRC-5, using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. PdL1 exhibited cytotoxic potency and selectivity against HeLa cell that was comparable to cisplatin's. Complex PdL1, unlike cisplatin, did not significantly induce caspase-dependent apoptosis.

Recent Studies on the Antimicrobial Activity of Transition Metal Complexes of Groups 6–12

Antimicrobial resistance is an increasingly serious threat to global public health that requires innovative solutions to counteract new resistance mechanisms emerging and spreading globally in infectious pathogens. Classic organic antibiotics are rapidly exhausting the structural variations available for an effective antimicrobial drug and new compounds emerging from the industrial pharmaceutical pipeline will likely have a short-term and limited impact before the pathogens can adapt. Inorganic and organometallic complexes offer the opportunity to discover and develop new active antimicrobial agents by exploiting their wide range of three-dimensional geometries and virtually infinite design possibilities that can affect their substitution kinetics, charge, lipophilicity, biological targets and modes of action. This review describes recent studies on the antimicrobial activity of transition metal complexes of groups 6–12. It focuses on the effectiveness of the metal complexes in relation to the rich structural chemical variations of the same. The aim is to provide a short vade mecum for the readers interested in the subject that can complement other reviews.

Substitution kinetics of platinum N,N,N’,N’-Tetrakis (2-pyridyl methyl) octane diamine aqua complex with thiourea, glutathione and L-cysteine nucleophiles

The ligand substitution kinetics of the platinum(II) complex, [Pt2(L)(OH2)2](ClO4)4 (L = N, N,N’,N’-tetrakis (2-pyridylmethyl) octane diamine) by a series of nucleophiles, viz. thiourea (TU), L-cystein (L-CYST), and glutathione (GLT) were investigated in 0.2 M NaClO4 ionic strength. The reactions were studied under pseudo-first order conditions at different temperatures and nucleophile concentrations. Reactions involving glutathione and L-cysteine were investigated using UV-Vis spectrophotomer while the faster reactions of thiourea were monitored on the stopped-flow spectrofluorimeter. Second order rate constants (M-1s-1) at 298 K are 0.194, 0.567, and 1.505 for GLT, L-CYST, and TU, respectively. The activation parameters obtained for the three nucleophiles in the same order of GLT, L-CYST, and TU, are ΔH≠ (kJ mol-1): 58.0, 13.0, 41.6 and ΔS≠ (J K-1 mol-1): -63.6, -206.1 and -101.8, respectively.

Kinetics of chloride substitution in the [Pt2(6NNpy)Cl4] complex by l-methionine

The studied platinum(II) complex is an example of bimetallic chlorido complexes. Its reaction with S-donor l-methionine results in substitution of chloride ligand by incoming nucleophile. A possible hydrolysis process is omitted due to addition of chlorides (10 mM) to the reaction mixture. The isosbestic point observed on the spectra of the reaction mixture shows that the studied process is a simple one-step substitution. It is in agreement with a one-exponential behavior of absorbance-time data. Dependency of the observed rate constant on l-methionine concentration is linear with non-zero intercept suggesting reversibility of the process. Activation parameters, i.e. positive ΔH≠ and strongly negative ΔS≠, suggest associative path of the forward and reverse reactions what is expected for substitution in square-planar platinum(II) complexes. The studied complex reacts with l-methionine faster than its quinoline analogue. It results from steric hindrances in the reaction of the latter complex as well as from higher electrophilicity of platinum(II) center in the [Pt2(6NNpy)Cl4] complex, described in this paper. The opposite tendency is observed for the reverse process. It can be explained taking into account lower stability of the quinoline complex with l-methionine than its pyridine analogue.

Kinetic and mechanistic studies of the transformation of the catalyst, tris(pentafluorophenyl)borane, in the presence of silyl and germyl hydrides

Tris(pentafluorophenyl)borane catalyzed Si-H bond activation opens the door to numerous transition-metal-free reduction processes and is widely used in organic and polymer chemistry. However, chemical stability of B(C6F5)3 in the presence of silyl hydrides is limited, which can strongly affect its catalytic activity. Transformations of B(C6F5)3 in the presence of phenyldimethylsilane, triethylsilane and triethylgermane were studied by 19F NMR and UV spectroscopy, GC/MS and quantum-mechanical calculations. The observed exchange of pentafluorophenyl group attached to boron to hydrogen results in the formation of bis(pentafluorophenyl)borane, which has a strongly reduced ability to activate the Si-H bond. The substitution kinetics were studied by following the disappearance of absorption of the B(C6F5)3 charge transfer peak in the UV spectrum. Complementary quantum mechanical calculations allowed us to propose a mechanism of the ligand exchange reaction, which involves electrophilic substitution of the pentafluorophenyl group through a four-center transition state.

Influence of steric and electronic effect of carrier ligand on kinetics & mechanism of Pt(II) complexes with l-cysteine and its substituted derivatives: Their experimental and DFT-based theoretical study

The present research work focuses on influences of steric and electronic effect on the kinetic and mechanistic investigation of the cytotoxic Pt(II) complexes with sulfur containing bio-molecules, which is relevant in order to understand the drug-reservoir activity of the complexes. To evaluate the steric and electronic effect of carrier ligand on substitution kinetics of Pt(II) complexes, 2° and 3° bidentate amine (DMEEDA) have been considered. Pt(II)-dichloro complex [Pt(DMEEDA)Cl2], 1 and its hydrolysed form [Pt(DMEEDA)(H2O)2](ClO4)2, 2 have been synthesised and characterised, wherein DMEEDA stands for N,N-Dimethyl-N′-ethylethylenediamine, a bidentate carrier ligand with different alkyl substituents. The diaqua platinum complex 2 has been considered for detailed kinetic investigation with biologically important intercellular thiol l-cysteine (l-cys) and its derivative N-acetyl-l-cysteine (N-ac-l-cys) under pseudo first order condition at pH 4.0 in aqueous medium. The product complexes [Pt(DMEEDA)(l-cys)](ClO4), 3 and [Pt(DMEEDA)(N-ac-l-cys)], 4 have been isolated and characterised. The activation parameters (ΔHǂ and ΔSǂ) for both the steps underlying the thiol assisted substitution reactions have been calculated. Theoretical Density Functional Theory (DFT) has been undertaken to optimise the complexes for HOMO-LUMO energy calculation, TD-DFT and natural bond orbital (NBO) analysis to strengthen the experimental findings. Various electronic properties of the complexes, called DFT-based descriptors have been calculated from frontier molecular orbital energies to predict their adduct formation ability with DNA. TD-DFT study has been undertaken to generate both the simulated spectra of UV–Vis and IR to compare with the corresponding experimental spectral results. To justify the chelation via (S,O), not through other possible modes, NBO analysis has been considered for the complex 3 and 4, which is also supported by spectroscopic observation.

Modelling of process of displacement of methane from gas hydrate reservoir at dioxide carbon injection

The paper presents a mathematical model for describing the process of displacing methane with carbon dioxide from a reservoir saturated with methane and its hydrate. For gas substitution kinetics, a scheme has been proposed in which the intensity of the process is defined by the diffusion of carbon dioxide through the hydrate layer formed between the gas mixture flow and methane hydrate. The numerical research of influence of main parameters on dynamics of process is conducted. Influence of coefficient of diffusion mixing of the gas mixture and permeability for the time of complete gas-replacement in reservoir is studied.