Understanding the Enzyme (S)-Norcoclaurine Synthase Promiscuity to Aldehydes and Ketones.

The (S)-norcoclaurine synthase from Thalictrum flavum (TfNCS) stereoselectively catalyzes the Pictet-Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. TfNCS can catalyze the Pictet-Spengler reaction with various aldehydes and ketones, leading to diverse tetrahydroisoquinolines. This substrate promiscuity positions TfNCS as a highly promising enzyme for synthesizing fine chemicals. Understanding carbonyl-containing substrates' structural and electronic signatures that influence TfNCS activity can help expand its applications in the synthesis of different compounds and aid in protein optimization strategies. In this study, we investigated the influence of the molecular properties of aldehydes and ketones on their reactivity in the TfNCS-catalyzed Pictet-Spengler reaction. Initially, we compiled a library of reactive and unreactive compounds from previous publications. We also performed enzymatic assays using nuclear magnetic resonance to identify some reactive and unreactive carbonyl compounds, which were then included in the library. Subsequently, we employed QSAR and DFT calculations to establish correlations between substrate-candidate structures and reactivity. Our findings highlight correlations of structural and stereoelectronic features, including the electrophilicity of the carbonyl group, to the reactivity of aldehydes and ketones toward the TfNCS-catalyzed Pictet-Spengler reaction. Interestingly, experimental data of seven compounds out of fifty-three did not correlate with the electrophilicity of the carbonyl group. For these seven compounds, we identified unfavorable interactions between them and the TfNCS. Our results demonstrate the applications of in silico techniques in understanding enzyme promiscuity and specificity, with a particular emphasis on machine learning methodologies, DFT electronic structure calculations, and molecular dynamic (MD) simulations.

Calculation of Excited State Internal Conversion Rate Constant Using the One-Effective Mode Marcus-Jortner-Levich Theory.

In this article, the one-effective mode Marcus-Jortner-Levich (MJL) theory and the classical Marcus theory for electron transfer were applied to estimate the internal conversion rate constant, kIC, of organic molecules and a Ru-based complex, all belonging to the Marcus inverted region. For this, the reorganization energy was calculated using the minimum energy conical intersection point to account for more vibrational levels, correcting the density of states. The results showed good agreement with experimental and theoretically determined kIC, with a small overestimation by the Marcus theory. Also, molecules less dependent on the solvent effects, like benzophenone, presented better results than molecules with an expressive dependence, like 1-aminonaphthalene. Moreover, the results suggest that each molecule possesses unique normal modes leading to the excited state deactivation that does not necessarily match the X-H bond stretching, as previously suggested.

New Hybrid Compound Candidate as Photothermal Agent Based on DPP Derivatives and Toluidine Blue: A Theoretical Perspective.

In this article, the synthesis of a new hybrid compound, candidate as photothermal agent, is proposed, based on TDPP (3,6-di(thiophene-2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione) and toluidine blue. Electronic structure calculations at the DFT, TD-DFT and CCSD level of theories were performed to obtain ground and excited states molecular structures, photophysical properties and absorption spectrum of the hybrid and the starting compounds. Additionally, ADMET calculations were performed to predict the pharmacokinetic, metabolic and toxicity properties of the proposed compound. The results showed that the proposed compound is a strong candidate for photothermal agent since (1) it absorbs close to the near-infrared region, (2) it has low fluorescence and intersystem crossing rate constants, (3) it has accessible conical intersection with low energy barrier, (4) the compound shows lower toxicity than the well know compound toluidine blue, which is used in photodynamic therapy, (5) the compound does not show carcinogenic potential, and (6) it obeys the Lipinski's rule of five, used as a reference for the design of new pharmaceuticals.

Theoretical investigation of [Ru(bpy)2(HAT)]2+ (HAT = 1,4,5,8,9,12-hexaazatriphenylene; bpy = 2,2'-bipyridine): Photophysics and reactions in excited state.

In this article, Density Functional Theory based calculations, including dispersion corrections, PBE0(D3BJ)/Def2-TZVP(-f), were performed to elucidate the photophysics of the [Ru(bpy)2(HAT)]2+ complex in water. In addition, the thermodynamics of the charge and electron transfer excited state reactions of this complex with oxygen, nitric oxide and Guanosine-5'-monophosphate nucleotide (GMP) were investigated. The first singlet excite state, S1, strongly couples with the second and third triplet excited states (T2 and T3) giving rise to a high intersystem crossing rate of 6.26 × 1011 s-1 which is ∼106 greater than the fluorescence rate decay. The thermodynamics of the excited reactions revealed that all electron transfer reactions investigated are highly favorable, due mainly to the high stability of the triply charged radical cation 2PS•3+ species formed after the electron has been transferred. Excited state electron transfer from the GMP nucleotide to the complex is also highly favorable (ΔGsol = -92.6 kcal/mol), showing that this complex can be involved in the photooxidation of DNA, in line with experimental findings. Therefore, the calculations allow to conclude that the [Ru(bpy)2(HAT)]2+ complex can act in Photodynamic therapy through both mechanisms type I and II, through electron transfer from and to the complex and triplet-triplet energy transfer, generating ROS, RNOS and through DNA photooxidation. In addition, the work also opens a perspective of using this complex for the in-situ generation of the singlet nitroxyl (1NO-) species, which can have important applications for the generation of HNO and may have, therefore, important impact for physiological studies involving HNO.

Computational insights into the reactivity of chlorpyrifos and chlorpyrifos-methyl toward singlet oxygen.

A complete mechanism for the •OH-initiated atmospheric decomposition of the pesticides chlorpyrifos and chlorpyrifos-methyl is proposed, incorporating additional studies on the competing reaction with singlet oxygen. The computational study is based on density functional theory (DFT) at the double-hybrid functional level to treat static correlation in the calculations of energy barriers. Reaction of the P-bonded intermediate with 1O2 has a small energy barrier of ~ 2 kcal mol-1, generating the Oxone compound and the HOSO• radical, with a reaction free energy of - 49.8 kcal/mol for the chlorpyrifos reaction pathway. Direct reaction of the pesticides with singlet oxygen is unlikely to happen due to the exceedingly high energy barrier of ~ 52 kcal/mol. However, in aqueous solution, the activation energy reduces dramatically and changes the reaction thermodynamics, making it kinetically accessible and thermodynamically viable.

Non-structural protein 5 (NS5) as a target for antiviral development against established and emergent flaviviruses.

Flaviviruses are among the most critical pathogens in tropical regions and cause a growing number of severe diseases in developing countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Among the ten proteins encoded in the flavivirus RNA, non-structural protein 5, NS5, is a promising drug target. NS5 plays a fundamental role in flavivirus replication, viral RNA methylation, RNA polymerization, and host immune system evasion. Most of the NS5 inhibitor candidates target NS5 active sites. However, the similarity of NS5 activity sites with human enzymes can cause side effects. Identifying new allosteric sites in NS5 can contribute enormously to antiviral development. The NS5 structural characterization enabled exploring new regions, such as the residues involved in MTase-RdRp interaction, NS5 oligomerization, and NS5 interaction with other viral and host-cell proteins. Targeting NS5 critical interactions might lead to new compounds and overcomes the toxicity of current NS5-inhibitor candidates.

Nitric Oxide Reacts Very Fast with Hydrogen Sulfide, Alcohols, and Thiols to Produce HNO: Revised Rate Constants.

The chemical reactivity of NO and its role in several biological processes seem well established. Despite this, the chemical reduction of •NO toward HNO has been historically discarded, mainly because of the negative reduction potential of NO. However, this value and its implications are nowadays under revision. The last reported redox potential, E'(NO,H+/HNO), at micromolar and picomolar concentrations of •NO and HNO, respectively, is between -0.3 and 0 V at pH 7.4. This potential implies that the one-electron-reduction process for NO is feasible under biological conditions and could be promoted by well-known biological reductants with reduction potentials of around -0.3 to -0.5 V. Moreover, the biologically compatible chemical reduction of •NO (nonenzymatic), like direct routes to HNO by alkylamines, aromatic and pseudoaromatic alcohols, thiols, and hydrogen sulfide, has been extensively explored by our group during the past decade. The aim of this work is to use a kinetic modeling approach to analyze electrochemical HNO measurements and to report for the first-time direct reaction rate constants between •NO and moderate reducing agents, producing HNO. These values are between 5 and 30 times higher than the previously reported keff values. On the other hand, we also showed that reaction through successive attack by two NO molecules to biologically compatible compounds could produce HNO. After over 3 decades of intense research, the •NO chemistry is still there, ready to be discovered.

Theoretical Investigation of the 4,5-Dibromorodamine Methyl Ester (TH9402) Photosensitizer Used in Photodynamic Therapy: Photophysics, Reactions in the Excited State, and Interactions with DNA.

Photosensitizer (PS) molecules play a critical role in photodynamic therapy of cancer and the understanding of the molecular mechanism involved in the photophysics of these compounds, and their reactions in the excited state are, therefore, of great interest for the development of this technique. In this article, the photophysics of the cationic PS 4,5-dibromorodamine methyl ester (TH9402), its electron- and energy-transfer reactions in the excited triplet state, with molecular oxygen, nitric oxide, guanosine-5'-monophosphate (GMP), and guanine, and the interaction with DNA were evaluated. Time-dependent density functional theory calculations at the TPSSh/Def2-TZVP//B3LYP/Def2-TZVP level of theory in water solution reveals that the PS has a bright S1 state 2.33 eV above the ground state that produces a fluorescent rate constant of 5.40 × 107 s-1, calculated using Fermi's golden rule within a path integral formalism. Once excited to the bright state, the main intersystem crossing (ISC) channel involves the coupling with the T2 state just below S1 (S1 → T2 → T1) with an overall ISC rate constant of 10.1 × 107 s-1, in good agreement with the experimental data. Excited-state reaction thermodynamics, computed at the M06-2X/Def2-TZVP//B3LYP/Def2-TZVP level of theory in water, showed that from all the excited-state electron-transfer reactions studied, only the transfer from GMP to the PS is thermodynamically favorable, independent of the protonation state of guanosine, which indicates a possible DNA photo-oxidation mechanism for the PS. Triplet-triplet energy-transfer reactions from TH9402 to molecular oxygen, producing reactive singlet oxygen, and to the deprotonated guanosine, producing 3GMP2-, are also thermodynamically favorable, with ΔG = -2.0 and -24.0 kcal//mol, respectively. However, the energy transfer to the monoprotonated guanosine is not favorable, (ΔG = 36.1), suggesting that in the DNA double-strand environment, this energy-transfer process may not be observed. The results show that the PS can act through electron transfer and triplet-triplet energy-transfer reactions involved in mechanism types I and II in photodynamic therapy. Interactions of TH9402 with the d(AGACGTCT)2 octanucleotide revealed that the PS can intercalate between the d(GpC)-d(CpG) base pairs in three different orientations and, upon intercalation, the π → π* transition of the PS shows a bathochromic shift up to 90 nm and up to 60% decrease in intensity. Interactions through groove binding showed a smaller bathochromic shift of 52.2 nm and a 56% decrease in intensity of the main transition band.

Electronic structure and mechanism for the uptake of nitric oxide by the Ru(iii) antitumor complex NAMI-A.

Nitric oxide (NO) has well known vasodilation effects in living organisms and its participation in the metastasis of cancer cells through the angiogenesis process has been demonstrated experimentally. Therefore, the uptake of NO has become one focus of investigation to produce anti-metastatic drugs. In this article we have investigated the uptake of NO by the ruthenium based metallodrug trans-tetrachloride(dimethylsulfoxide)imidazole ruthenate(iii) [Im]trans-[RuCl4(Im)(DMSO)], known as New Anti-tumor Metastasis Inhibitor-A (NAMI-A). Electronic structure calculations using Density Functional Theory, DFT, and State-Averaged Complete Active Space Self Consistent Field, SA-CASSCF, with second order perturbation theory corrections, NEVPT2 were carried out to investigate the mechanism involved in the uptake of NO by the Ru-based anticancer metallodrug NAMI-A. The calculations revealed that the reaction takes place at the triplet potential energy surface, with the singlet surface being ∼15 kcal mol-1 shifted to higher energies, and there is a surface crossing to form the most stable singlet product after the reaction takes place at the triplet surface. The spin pairing and electron transfer from the nitric oxide to the metallic fragment takes place at the region of the minimum energy crossing point between the two surfaces. The Ru-NO bond in the {Ru-NO}6 product has ∼10% of the RuIII-NO0 character. The SA-CASSCF/NEVPT2 calculations revealed that the uptake of NO by NAMI-A has a small energy barrier of ∼8 kcal mol-1 and, therefore a rate constant of 11.3 × 106 s-1 at 300 K. In addition, the reaction is thermodynamically favorable, with a Gibbs free energy of ∼30 kcal mol-1. These results show that the uptake of nitric oxide by the NAMI-A complex is kinetically and thermodynamically feasible in biological medium and, therefore, gives support to the anti-angiogenesis theory associated to the mode of action of NAMI-A and other related compounds.

Revisiting the Tropospheric OH-Initiated Unimolecular Decomposition of Chlorpyrifos and Chlorpyrifos-Methyl: A Theoretical Perspective.

Based on density functional theory (DFT) electronic structure calculations with dispersion correction, we propose new reaction pathways in which no extra reaction step is necessary to account for the formation of 3,5,6-trichloro-2-pyridynol (TCP) within the process of tropospheric OH-initiated unimolecular decomposition of chlorpyrifos (CLP) and chlorpyrifos-methyl (CLPM). Chlorpyrifos and its analogous compound are among the most used organophosphorus pesticides worldwide, and their unimolecular decomposition in the troposphere is a dominant process of removal in the gas phase. The reaction pathways that we put forward have turned out to be the most exergonic ones among the three possible routes for the attack of the hydroxyl radical to the thiophosphoryl (P═S) bond of both CLP and CLPM. The results showed that the reaction is thermodynamically controlled with the formation of P-bonded adducts via a six-membered ring. The unimolecular decomposition of such reactive intermediates takes place with small energy barriers (less than 3 kcal mol-1) and is distinguished by hydrogen transfer to the nitrogen atom of the aromatic ring, resulting in the formation of 3,5,6-trichloro-2-pyridinol (TCP) and dialkyl phosphate radical (DAP·) product complexes in a single step.

NO/H2S "Crosstalk" Reactions. The Role of Thionitrites (SNO-) and Perthionitrites (SSNO-).

The redox chemistry of H2S with NO and other oxidants containing the NO group is discussed on a mechanistic basis because of the expanding interest in their biological relevance, with an eye open to the chemical differences of H2S and thiols RSH. We focus on the properties of two "crosstalk" intermediates, SNO- (thionitrite) and SSNO- (perthionitrite, nitrosodisulfide) based in the largely controversial status on their identity and chemistry in aqueous/nonaqueous media, en route to the final products N2O, NO2-, NH2OH/NH3, and S8. Thionitrous acid, generated either in the direct reaction of NO + H2S or through the transnitrosation of RSNO's (nitrosothiols) with H2S at pH 7.4, is best described as a mixture of rapidly interconverting isomers, {(H)SNO}. It is reactive in different competitive modes, with a half-life of a few seconds at pH 7.4 for homolytic cleavage of the N-S bond, and could be deprotonated at pH values of up to ca. 10, giving SNO-, a less reactive species than {(H)SNO}. The latter mixture can also react with HS-, giving HNO and HS2- (hydrogen disulfide), a S0(sulfane)-transfer reagent toward {(H)SNO}, leading to SSNO-, a moderately stable species that slowly decomposes in aqueous sulfide-containing solutions in the minute-hour time scale, depending on [O2]. The previous characterization of HSNO/SNO- and SSNO- is critically discussed based on the available chemical and spectroscopic evidence (mass spectrometry, UV-vis, 15N NMR, Fourier transform infrared), together with computational studies including quantum mechanics/molecular mechanics molecular dynamics simulations that provide a structural and UV-vis description of the solvatochromic properties of cis-SSNO- acting as an electron donor in water, alcohols, and aprotic acceptor solvents. In this way, SSNO- is confirmed as the elusive "yellow intermediate" (I412) emerging in the aqueous crosstalk reactions, in contrast with its assignment to polysulfides, HSn-. The analysis extends to the coordination abilities of {(H)SNO}, SNO-, and SSNO- into heme and nonheme iron centers, providing a basis for best unraveling their putative specific signaling roles.

[Ag(L)NO3] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.

Complexes [Ag(H2BzPh)NO3] (1), [Ag(H2BzpCH3Ph)NO3] (2), [Ag(H2BzpClPh)NO3] (3), and [Ag(H2BzpNO2Ph)NO3] (4) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its para-methyl-benzoylhydrazone (H2BzpCH3Ph), para-chloro-benzoylhydrazone (H2BzpClPh), and para-nitro-benzoylhydrazone (H2BzpNO2Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (1-3) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC50 non-malignant cells/IC50 tumor cells) of complex (1), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (1-3) with DNA suggested that although (1-3) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver(I) to DNA probably does not occur. Complexes (1-3) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin.

Theoretical investigation of the neutral hydrolysis of diethyl 4-nitrophenyl phosphate (paraoxon) in aqueous solution.

In this work the neutral or spontaneous hydrolysis of paraoxon, one of the most popular organophosphate pesticides, in aqueous solution was investigated at the DFT and MP2 levels of theory, using a combination of local solvation of the phosphoryl group with explicit water molecules, and treating the long range solvent effects using continuum solvation model. In contrast to the alkaline hydrolysis, the neutral hydrolysis takes place in two steps, through an AN + DN mechanism, with formation of a pentacoordinate phosphorane intermediate. The reaction has activation free energies of 31.8 and 1.9 kcal mol-1 for the first and second steps, respectively, and has an overall reaction free energy of -9.3 kcal mol-1, computed at the MP2/6-311++G(2d,2p)//B3LYP/6-31+G(d) level of theory. The reaction proceeds through a sequence of proton transfer processes from the attacking water molecule and ends with the protonation of the nitrophenolate leaving group. Explicit description of the local solvating water molecules is essential to describe the proton transfer processes along the reaction coordinate and to stabilize the pentacoordinate intermediate formed. The neutral hydrolysis is very slow and has an overall rate constant of 3.05 × 10-11 s-1, computed at the MP2/6-311++G(2d,2p)//B3LYP/6-31+G(d) level of theory. This result, in conjunction with the sensitivity of the rate constant to the experimental conditions, indicates that the hydrolysis of paraoxon in aqueous solution can be even slower than predicted experimentally.

Base Mechanism to the Hydrolysis of Phosphate Triester Promoted by the Cd2+/Cd2+ Active site of Phosphotriesterase: A Computational Study.

In the present work, density functional theory (DFT) calculations at the B3LYP/6-31+G(d) and including dispersion effects were used to investigate the hydrolysis of paraoxon, using a cluster model of the active site of Cd2+/Cd2+-phosphotriesterase (PTE) from Pseudomonas diminuta. The mechanism proposed here consist of (i) Exchange of the coordinated water molecule and coordination of the substrate to the more solvent exposed Cdß center in monodentate fashion, (ii) protonation of the µ-hydroxo bridge by the uncoordinated water molecule and in situ formation of the nucleophile, (iii) formation of a pentacoordinate intermediate with significant bond breaking to the leaving group and bond formation to the nucleophile, and (iv) protonation of the Asp301 residue and restoration of the active site through the coordination of another water molecule of the medium. The water molecules initially coordinated to the active site play a crucial role in stabilizing the transition states and the pentacoordinate intermediate. The reaction takes place in a two-step (AN + DN) mechanism, with energy barriers of 12.9 and 1.9 kcal/mol for the first and second steps, respectively, computed at the B3LYP-D3/6-311++G(2d,2p) level of theory, in excellent agreement with the experimental findings. Dispersion effects alone contribute to diminish the energy barriers as much as 26%. The base mechanism for the Cd2+/Cd2+-PTE proposed here, in conjunction with the agreement found with the experimental energetic value for the energy barrier, makes it a consistent and kinetically viable mechanistic proposal for the hydrolysis of phosphate triesters promoted by the Cd2+ substituted PTE enzyme.

Correction to [Ag(L)NO3] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.

[This corrects the article DOI: 10.1021/acsomega.8b00533.].

HNO Is Produced by the Reaction of NO with Thiols.

Azanone (nitroxyl, HNO) is a highly reactive compound whose biological role is still a matter of debate. One possible route for its formation is NO reduction by biological reductants. These reactions have been historically discarded due to the negative redox potential for the NO,H+/HNO couple. However, the NO to HNO conversion mediated by vitamins C, E, and aromatic alcohols has been recently shown to be feasible from a chemical standpoint. Based on these precedents, we decided to study the reaction of NO with thiols as potential sources of HNO. Using two complementary approaches, trapping by a Mn porphyrin and an HNO electrochemical sensor, we found that under anaerobic conditions aliphatic and aromatic thiols (as well as selenols) are able to convert NO to HNO, albeit at different rates. Further mechanistic analysis using ab initio methods shows that the reaction between NO and the thiol produces a free radical adduct RSNOH•, which reacts with a second NO molecule to produce HNO and a nitrosothiol. The nitrosothiol intermediate reacts further with RSH to produce a second molecule of HNO and RSSR, as previously reported.

Solvation and Proton-Coupled Electron Transfer Reduction Potential of 2NO• to 1HNO in Aqueous Solution: A Theoretical Investigation.

In this work, quantum mechanical calculations and Monte Carlo statistical mechanical simulations were carried out to investigate the solvation properties of HNO in aqueous solution and to evaluate the proton-coupled one electron reduction potential of 2NO to 1HNO, which is essential missing information to understand the fate of 2NO in the biological medium. Our results showed that the 1HNO molecule acts mainly as a hydrogen bond donor in aqueous solution with an average energy of -5.5 ± 1.3 kcal/mol. The solvation free energy of 1HNO in aqueous solution, computed using three approaches based on the linear response theory, revealed that the current prediction of the hydration free energy of HNO is, at least, 2 times underestimated. We proposed two pathways for the production of HNO through reduction of NO. The first pathway is the direct reduction of NO through proton-coupled electron transfer to produce HNO, and the second path is the reduction of the radical anion HONO•-, which is involved in equilibrium with NO in aqueous solution. We have shown that both pathways are viable processes under physiological conditions, having reduction potentials of E°' = -0.161 V and E°' ≈ 1 V for the first and second pathways, respectively. The results shows that both processes can be promoted by well-known biological reductants such as NADH, ascorbate, vitamin E (tocopherol), cysteine, and glutathione, for which the reduction potential at physiological pH is around -0.3 to -0.5 V. The computed reduction potential of NO through the radical anion HONO•- can also explain the recent experimental findings on the formation of HNO through the reduction of NO, promoted by H2S, vitamin C, and aromatic alcohols. Therefore, these results contribute to shed some light into the question of whether and how HNO is produced in vivo and also for the understanding of the biochemical and physiological effects of NO.

Water Solvent Effect on Theoretical Evaluation of 1H NMR Chemical Shifts: o-Methyl-Inositol Isomer.

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of 1H NMR spectra. In order to include explicit water molecules, 20 water-l-quebrachitol configurations obtained from Monte Carlo simulation were selected to perform geometry optimizations using the effective fragment potential method encompassing 60 water molecules around the solute. The solvated solute optimized geometries were then used in B3LYP/6-311+G(2d,p) NMR calculations with PCM-water. The inclusion of explicit solvent in the B3LYP NMR calculations resulted in large changes in the 1H NMR profiles. We found a remarkable improvement in the agreement with experimental NMR profiles when the explicit hydrated l-quebrachitol structure is used in B3LYP 1H NMR calculations, yielding a mean absolute error (MAE) of only 0.07 ppm, much lower than reported previously for the gas phase optimized structure (MAE = 0.11 ppm). In addition, a very improved match between theoretical and experimental 1H NMR spectrum measured in D2O was achieved with the new hydrated optimized l-quebrachitol structure, showing that a fine-tuning of the theoretical NMR spectra can be accomplished once solvent effects are properly considered.

Cytotoxic and antimicrobial effects of indium(iii) complexes with 2-acetylpyridine-derived thiosemicarbazones.

Complexes [In(2Ac4oClPh)Cl2(MeOH)] (1), [In(2Ac4pFPh)Cl2(MeOH)] (2), [In(2Ac4pClPh)Cl2(MeOH)] (3) and [In(2Ac4pIPh)Cl2(MeOH)] (4) were obtained with N(4)-ortho-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4oClPh), N(4)-para-fluorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pFPh), N(4)-para-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pClPh) and N(4)-para-iodophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pIPh). Theoretical studies suggested that the coordinated methanol molecule can be easily replaced by DMSO used in the preparation of stock solutions, with the formation of [In(L)Cl2(DMSO)] (HL = thiosemicarbazonate ligand), and that the replacement of DMSO by water is unfavorable. However, for all complexes the displacement of one or two chloride ligands by water in aqueous solution is extremely favorable. The cytotoxic activity of the compounds was evaluated against HL-60, Jurkat and THP-1 leukemia and against MDA-MB-231 and HCT-116 solid tumor cell lines, as well as against Vero non-malignant cells. The cytotoxicity and selectivity indexes (SI) increased in several cases for the indium(iii) complexes in comparison with the free thiosemicarbazones. The antimicrobial activity of the compounds was investigated against Candida albicans, Candida dubliniensis, Candida lusitaniae and Candida parapsilosis. In many cases complexation resulted in a substantial increase of the antifungal activity. Complexes (1-4) were revealed to be very active against C. lusitaniae and C. dubliniensis. Structure-activity relationship (SAR) studies were carried out to identify the physico-chemical properties that might be involved in the antifungal action, as well as in the cytotoxic effect of the compounds against HL-60 cells. In both cases, correlations between the bioactivity and physico-chemical properties did not appreciably change when the chloride ligands in [In(L)Cl2(DMSO)] were replaced by water molecules, suggesting [In(L)Cl(H2O)(DMSO)]+ or [In(L)(H2O)2(DMSO)]2+ to be the species that interact with the biological media.

Formation and Release of NO from Ruthenium Nitrosyl Ammine Complexes [Ru(NH3)5(NO)]2+/3+ in Aqueous Solution: A Theoretical Investigation.

In this article, density functional theory in conjunction with Monte Carlo statistical mechanical simulation was used to investigate the electronic structure, reduction potential, solvation, and solvent effects on the electronic spectra of nitrosyl ammine complexes using [Ru(NH3)5(NO)]2+/3+ as model compounds. In addition, ligand exchange reactions with solvent water molecules were also investigated. It is shown that the complexes are involved in strong hydrogen bonds in aqueous solution, with mean average energies of -13.5 ± 0.4 and -22.4 ± 0.4 kcal mol-1 for Ru(II) and Ru(III), respectively. Interestingly, for all the complexes studied, the NO ligand is not involved in hydrogen bonding interactions in aqueous solution. These strong hydrogen bonds are responsible for the high stability of these complexes in aqueous solution, showing formation constants Kf greater than 1021. The complex [Ru(NH3)5(NO)]3+ can easily be reduced by biological reducing agents in both the singlet and triplet states; however, the reduction is easier in the triplet state, which has a positive reduction potential of 1.70 V. The formation of [Ru(NH3)5(NO)]3+ in its most stable singlet state may take place through at least two singlet-triplet surface crossings leading to nonadiabatic effects. The existence of the minimum-energy crossing points makes the release of NO from the triplet state more favorable, with an activation energy almost seven times lower (∼6 kcal mol-1).