Exocyclic Oxygen Atom Research Articles

Electronic relaxation pathways in thio-acridone and thio-coumarin: two heavy-atom-free photosensitizers absorbing visible light.

Heavy-atom-free photosensitizers (HAF-PSs) have emerged as a new class of photosensitizers aiming to broaden their applicability and versatility across various fields of the photodynamic therapy of cancers. The strategy involves replacing the exocyclic oxygen atoms of the carbonyl groups of established biocompatible organic fluorophores with sulfur, thereby bathochromically shifting their absorption spectra and enhancing their intersystem crossing efficiencies. Despite these advancements, the photophysical attributes and electronic relaxation mechanisms of many of these HAF-PSs remain inadequately elucidated. In this study, we investigate the excited state dynamics and photochemical properties of two promising HAF-PSs, thio-coumarin and thio-acridone. Employing a combination of steady-state and time-resolved techniques from femtoseconds to microseconds, coupled with quantum chemical calculations, we unravel the electronic relaxation mechanisms that give rise to the efficient population of long-lived and reactive triplet states in these HAF-PSs.

Synthetic approach to spiropyranocoumarins and their oxime derivatives

This study explores the synthesis of a diverse series of linear (spiro)pyranocoumarins and their corresponding oximes, compounds known for their promising biological activities. Building on previous work, the authors expand the array of target compounds, adding structural features such as dimethyl groups and various cycloaliphatic rings. The novel synthetic procedure applied herein couples o-hydroxyacetyl coumarins with respective ketones via Kabbe condensation, yielding 16 derivatives, including 12 new compounds. A further step engages these (spiro)pyranocoumarins with hydroxylamine hydrochloride, leading to oximes, selectively at the exocyclic oxygen atom of the chroman-4-one fragment. Optimizing synthesis conditions has increased product yields and reduced reaction times. Acidic hydrolysis of select compounds introduces additional carbonyl groups and facilitates deprotection, while the subsequent reaction with hydroxylamine hydrochloride produces dual-oxime compounds. These findings contribute to the ongoing development of pyranocoumarin and oxime-based therapeutics, with potential applications in treating various diseases

Synthesis of C7/C8-cyclitols and C7N-aminocyclitols from maltose and X-ray crystal structure of Streptomyces coelicolor GlgEI V279S in a complex with an amylostatin GXG-like derivative.

C7/C8-cyclitols and C7N-aminocyclitols find applications in the pharmaceutical sector as α-glucosidase inhibitors and in the agricultural sector as fungicides and insecticides. In this study, we identified C7/C8-cyclitols and C7N-aminocyclitols as potential inhibitors of Streptomyces coelicolor (Sco) GlgEI-V279S based on the docking scores. The protein and the ligand (targets 11, 12, and 13) were prepared, the states were generated at pH 7.0 ± 2.0, and the ligands were docked into the active sites of the receptor via Glide™. The synthetic route to these targets was similar to our previously reported route used to obtain 4-⍺-glucoside of valienamine (AGV), except the protecting group for target 12 was a p-bromobenzyl (PBB) ether to preserve the alkene upon deprotection. While compounds 11–13 did not inhibit Sco GlgEI-V279S at the concentrations evaluated, an X-ray crystal structure of the Sco GlgE1-V279S/13 complex was solved to a resolution of 2.73 Å. This structure allowed assessment differences and commonality with our previously reported inhibitors and was useful for identifying enzyme–compound interactions that may be important for future inhibitor development. The Asp 394 nucleophile formed a bidentate hydrogen bond interaction with the exocyclic oxygen atoms (C(3)-OH and C(7)-OH) similar to the observed interactions with the Sco GlgEI-V279S in a complex with AGV (PDB:7MGY). In addition, the data suggest replacing the cyclohexyl group with more isosteric and hydrogen bond–donating groups to increase binding interactions in the + 1 binding site.

Cytosine as a root to a nonconventional layered hydroxide nanostructure

A self-assembled layered compound of formula {[Cu5(OH)8Cyt2]·2ClO4} n (1) was obtained from the direct reaction between copper perchlorate and cytosine. Thanks to its peculiar structural features, this coordination compound can be classified as an intermediate nonconventional analog of Layered Simple Hydroxides (LSHs) and Layered Double Hydroxides (LDHs), two fascinating classes of inorganic materials with variable chemical composition and structures. Like LDHs, 1 consists of positively charged layers of metal hydroxides and non-framework charge-balancing anions located between the layers. However, the hydroxide layers, similar to LSHs, contain only divalent copper(II) metal ions, supported by cytosine molecules with long contacts. Cytosine coordinates to the metal centers adopting an unusual µ3 coordination mode, the exocyclic oxygen atom simultaneously binding to three adjacent copper(II) centers. This coordination mode has not been observed with transition metal ions. This work further demonstrates that nucleobases and their derivatives, despite presenting a limited pool of molecules, can potentially afford a significantly expanded set of compounds with diverse nanostructures, owing to their multiple metal binding sites of different coordination properties and their ability to direct assembly of highly ordered structures. Their potential as building blocks should be further explored for the preparation of new bio-inorganic hybrid materials.

Synthesis and NMR spectroscopy investigations of functionalized spiropyranochromenediones and their spirothiadiazole derivatives

This investigation focuses on the synthesis of spiropyranoneoflavones and the modification of obtained compounds at the exocyclic oxygen atom. Kabbe cyclization of 6-acetyl-7‑hydroxy-8-methyl-4-phenyl-2H-chromene-2-one with cyclohexanone or cyclopentanone in the presence of pyrrolidine provided 10-methyl-4-phenyl-2H-spiro[cyclohexane(cyclopentane)-1’,8-pyrano[3,2-g]chromene]-2,6(7H)-diones. Their new functionalized derivatives with thiosemicarbazide residues were synthesized. Acetylation of obtained thiosemicarbazones with acetic anhydride proceeded via cyclization of thiosemicarbazide fragment into 1,3,4-thiadiazole ring to give corresponding N-[3'-acetyl-10-methyl-8-oxo-6-phenyl-3'H,8H-dispiro[cyclohexane-1,2’-pyrano[3,2-g]chromene-4,2'-[1,3,4]thiadiazol]-5'-yl]acetamide and N-[3'-acetyl-10-methyl-8-oxo-6-phenyl-3'H,8H-dispiro[cyclopentane-1,2’-pyrano[3,2-g]chromene-4,2'-[1,3,4]thiadiazol]-5'-yl]acetamide. The structure of the obtained compounds was confirmed by NMR spectroscopy

Synthesis and Structural Characterization of Palladium(II) Mixed-Ligand Complexes of N-(Benzothiazol-2-yl)benzamide and 1,2-Bis(diphenylphosphino)ethane.

Three novel palladium(II) mixed-ligand complexes of N-(benzothiazol-2-yl)benzamide (HL) and 1,2-bis(diphenylphosphino)ethane (dppe), [Pd(HL)(dppe)]Cl2 (1), [Pd(L)(dppe)]Cl (2), and [Pd(L)2(dppe)] (3), were synthesized and fully characterized using Fourier transform infrared, 1H, 13C, and 31P NMR, and molar conductivity measurements. Complex 3 was characterized by single-crystal X-ray diffraction. The ligand HL showed three different coordination modes: a neutral bidentate chelate bound through the endocyclic nitrogen and exocyclic oxygen atoms in 1, a negatively charged L bound as a bidentate chelate through the endocyclic nitrogen and negatively charged exocyclic oxygen atoms in 2, and a monodentate bound through the negatively charged endocyclic nitrogen atom in 3.

Synthesis, characterization and H2 uptake of novel Hg(II) complexes containing 1,4-benzothiazin-3-one

Abstract Treatment of 1,4-benzothiazin-3-one (Hbto) with mercury(II) acetate Hg(OAc)2 in 2:1 mol ratio affords [Hg(bto)2] (1) in 99% yield. The resulted complex was used as a synthon to prepare new mixed-ligand complexes with monophosphines or diphosphines of the types [Hg(bto)2(L)2] or [Hg(bto)2(L-L)]; where L = triphenylphosphine (Ph3P) (2) or triphenylphosphinesulfide (Ph3PS) (3); L-L = 1,2-bis(diphenylphosphino)ethane (dppe) (4) or 1,1′-bis(diphenylphosphine)ferrocene (dppf) (5). FTIR, 1H NMR, 13C NMR, 31P-{1H} NMR, molar conductivity and elemental analysis were used to characterize the resulted complexes. Results suggest that 'bto' ion in [Hg(bto)2] (1) is linked to mercury ion via exocyclic oxygen and endocyclic nitrogen atoms in a chelating bidentate fashion while in the complexes (2–5), it is linked to mercury ion via endocyclic nitrogen atom in a monodentate fashion. Furthermore, to take benefit of mercury complexes which were classified as toxic compounds, [Hg(bto)2] (1) complex has been evaluated for its susceptibility to hydrogen storage. The result of H2 storage showed that this complex can store 1.42 wt% of hydrogen under 88 bar and 77 K.

The equilibrium molecular structure of 3-methyl-4-nitro- and 4-methyl-3-nitrofuroxans by gas-phase electron diffraction and coupled cluster calculations

The equilibrium molecular structures of the isomeric 3-methyl-4-nitro- and 4-methyl-3-nitrofuroxans have been determined for the first time by gas-phase electron diffraction (GED) supported by coupled cluster calculations up to CCSD(T)/cc-pVTZ level of theory, in frame of dynamic model with relaxation of all structural parameters. The best fit of the experimental scattering intensities was obtained for a model of Cs symmetry. The small differences between similar geometric parameters were constrained at the theoretical values. To compare structural parameters of the titled compounds, the geometries of parent furazan and furoxan molecules were calculated at the CCSD(T)-AE/aug-cc-pVQZ and CCSD(T)-AE/cc-pVQZ levels of theory, respectively. Mean amplitudes and vibrational corrections necessary for GED analysis were computed at the B3LYP/SNDS levels of theory using quadratic and cubic force fields. Peculiar features of electronic and geometric structures of the studied isomeric nitrofuroxans were analyzed with the use of different topological, magnetic and orbital descriptors and the reasons of the significant distinctions between 4- and 3-nitroisomers structures were revealed. Due to hyperconjugation a lone electron pair of exocyclic oxygen atom in both isomers was found to delocalize into antibonding orbital of adjacent ON endocyclic bond, nπ(O)→σ∗(ON). The peculiarity of the 3-nitroisomer structure was provided with the additional interaction of exocyclic and nitro group oxygen atoms.

Cytotoxic Activity of Organotin(IV) Derivatives with Triazolopyrimidine Containing Exocyclic Oxygen Atoms.

In this study cytotoxicity of organotin(IV) compounds with 1,2,4-triazolo[1,5-a]pyrimidines, Me3Sn(5tpO) (1), n-Bu3Sn(5tpO) (2), Me3Sn(mtpO) (3), n-Bu3Sn(mtpO) (4), n-Bu3Sn(HtpO2) (5), Ph3Sn(HtpO2) (6) where 5HtpO = 4,5-dihydro-5-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, HmtpO = 4,7-dihydro-5-methyl-7-oxo-[1,2,4]triazolo-[1,5-a]pyrimidine, and H2tpO2 = 4,5,6,7-tetrahydro-5,7- dioxo-[1,2,4]triazolo-[1,5-a]-pyrimidine, was assessed on three different human tumor cell lines: HCT-116 (colorectal carcinoma), HepG2 (hepatocarcinoma) and MCF-7 (breast cancer). While 1 and 3 were inactive, compounds 2, 4, 5 and 6 inhibited the growth of the three tumor cell lines with IC50 values in the submicromolar range and showed high selectivity indexes towards the tumor cells (SI > 90). The mechanism of cell death triggered by the organotin(IV) derivatives, investigated on HCT-116 cells, was apoptotic, as evident from the externalization of phosphatidylserine to the cell surface, and occurred via the intrinsic pathway with fall of mitochondrial inner membrane potential and production of reactive oxygen species. While compound 6 arrested the cell progression in the G2/M cell cycle phase and increased p53 and p21 levels, compounds 2, 4 and 5 blocked cell duplication in the G1 phase without affecting the expression of either of the two tumor suppressor proteins. Compounds 1 and 2 were also investigated using single crystal X-ray diffraction and found to be, in both cases, coordination polymers forming 1 D chains based on metal-ligand interactions. Interestingly, for n-Bu3Sn(5tpO)(2) H-bonding interactions between 5tpO− ligands belonging to adjacent chains were also detected that resemble the “base-pairing” assembly and could be responsible for the higher biological activity compared to compound 1. In addition, they are the first example of bidentate N(3), O coordination for the 5HtpO ligand on two adjacent metal atoms.

A new era of the prototropic tautomerism of the quercetin molecule: A QM/QTAIM computational advances

In this study for the first time we have revealed and investigated in details 123 different prototropic tautomers of the most stable conformer of the quercetin molecule using quantum-mechanical calculations at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of QM theory. We have found that in the most energetically favorable prototropic tautomer mobile hydrogen atoms are localized at the О3, О3′, О4′, О5, and О7 exocyclic oxygen atoms. Molecular tautomers are in the range of the Gibbs free energies from 0.0 to 69.8 kcal·mol−1, while zwitterionic ones – from 30.1 до 172.8 kcal·mol−1 at normal conditions. It was also reliably established that the weakest point causing the decyclization of the molecule is its C ring – this reaction is launched by the transition of the proton from the C8H group to the endocyclic O1 oxygen atom. All prototropic tautomers, except two cases, are joined by the intramolecular cooperative specific interactions (from 1 to 5) – H-bonds and attractive van der Waals contacts, which have been revealed and characterized by QTAIM analysis. Communicated by Ramaswamy H. Sarma

H2 storage abilities of some novel Pd(II) complexes containing 2H[1,4]benzothiazin-3(4H)-one

Initially, a novel series of mixed ligand Pd(II) complexes of 2H[1,4]benzothiazin-3(4H)-one (Hbto) and diamine or phosphine ligands were successfully prepared with yields of 61 to 92%. The treatment of Na2PdCl4 with Hbto in acetone with 1:2 Pd to Hbto ratio affords cis-[PdCl2(Hbto)2] (1) that delivers an appropriate entry into mixed-ligand Hbto complexes. The complex (1) was used as a precursor for preparation the complexes of the type [Pd(Hbto)2(κ2-diamine)]Cl2; (diamine = en (2a), bipy (2b), phen (2c)) and [Pd(Hbto)2(κ2-diphosphine)]Cl2; (diphosphine = dppm (3a), dppe (3b), dppp (3c), dppf (3d)). Likewise, the mono phosphine (PPh3) was used to prepare the contrast complex with complex (1), however, to dissipate the suspicion that define complex [Pd(Hbto)2(PPh3)2]Cl2 is present in the cis or trans structure, two methods were used to prepare this complex, both of which demonstrated that the cis is the preferred structure for the complex [Pd(Hbto)2(PPh3)2]Cl2 (4). For all as-prepared complexes, the characterization techniques (molar conductivity, IR, 1H-, 13C-{1H}, 31P-{1H}NMR and elemental analyses) prove that the Hbto links to Pd(II) in a mono-dentate fashion through the exocyclic oxygen atom. To benefit from the complexes prepared, some as-prepared complexes (1), (2b) and (4) have been evaluated for their H2 storage at 77 K after measuring the N2 adsorption/desorption isotherms in order to get some information about BET surface areas of the samples. The results demonstrate that the selected prepared complexes were all able of storing the H2 and among the complexes (1), (2b) and (4), (2b) was the best one and was able to store 5.4 wt% of H2 under 70 bar and 77 K.

MESOIONIC SYDNONE: A REVIEW IN THEIR CHEMICAL AND BIOLOGICAL PROPERTIES

Various literature sources have documented sydnones as important molecules with exclusive chemical properties and a wide spectrum of bioactivities. Sydnone can be defined as a five-membered pseudo-aromatic heterocyclic molecule. Classically, 1,2,3-oxadiazole forms the main skeleton of sydnone. The molecule has delocalized balanced positive and negative charges. The five annular atoms share the positive charge and the enolate-like exocyclic oxygen atom bears the negative charge. The hydrogen atom at the position C4 was proved to have acidic and nucleophilic functionalities making the sydnone ring reactive towards electrophilic reagents. These unique chemical features enable sydnones to interact with biomolecules resulting in important therapeutic effects like anticancer, antidiabetic, antimicrobial, antioxidant and anti-inflammatory. Consequently, we aim from the current article to review the available chemical and pharmacological information on sydnone and its derivatives.

ВПЛИВ Eu(fod)3 НА СПЕКТРИ 1Н ЯМР 3-АРИЛІЗОКУМАРИНІВ ТА 3-АРИЛ-3,4 ДИГІДРОІЗОКУМАРИНІВ З АЛКОКСИЛЬНИМИ, ЕСТЕРНИМИ ТА АМІДНИМИ ГРУПАМИ

The effect of the lanthanide shift reagent (LSR) – tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octa-dionate) of Europium – Eu(fod)3 – on 1H NMR spectra of functionalized 3-arylisocoumarins and 3-aryl-3,4-dihydroisocoumarins was investigated. Based on previous studies of LSR interactions with benzopyrones, it was expected that the main coordination centre for the Eu3+ would be the exocyclic Oxygen atom of the heterocycle, but the possibility of competition from aromatic substituent functional groups was also considered. By measuring lanthanide-induced shifts (LIS) of the proton signals of the molecules at different ratios of substrate and Eu(fod)3, specific LIS values were determined. Based on those, it was concluded that the main direction of LSR coordination with 3-(2-hydroxy-5-methylphenyl)-1Hisochromen-1-one, 3-(2-methoxy-5-methylphenyl)-1H-isochromen-1-one and 3-(2-methoxy-5-methylphenyl)isochroman-1-one is the exocyclic Oxygen atom of the heterocycle, because the maximum LIS were recorded for the H-8 atom of isochromone system of these derivatives. In the case of ethyl ester of [2-(4-(1-oxo-1H-isochromen-3-yl)phenoxy] acetic acid and methyl ester of [2-(4-(1-oxoisochroman-3-yl)phenoxy]acetic acid comparable LIS values were observed both for H-8 and for the methylene group of the hydroxyacetic acid fragment, therefore, in such molecules the coordination of the Eu3+ to the heterocycle or to the aliphatic ester group is almost equally probable. In spectrum of methyl ester of N-{[4-(1-oxo-1H-isochromen-3-yl)phenoxy]acetyl}valine and N-{[4-(1-oxoisochroman-3-yl)-phenoxy]acetyl}valine there are insignificant LIS of H-8; and the maximum LIS were observed for the signals of the protons neighboring the two carbonyl groups of hydroxyacetic acid and valine fragments. Thus, these compounds interact w

Alkylation reactions of 5-amino-substituted tetrazolo[1,5-a][1,3,5]triazin-7(3H)-ones with alkyl halides

The alkylation reactions of fused tetrazolo[1,5-a][1,3,5]triazine system were studied. The results of quantum-chemical calculations for the reaction of 5-(dimethylamino)tetrazolo[1,5-a][1,3,5]triazin-7(3H)-one with ethyl bromide are presented. The reactions of 5-aminosubstituted tetrazolo[1,5-a][1,3,5]triazin-7(3H)-ones with ethyl-, butyl-, and allyl halides led to the formation of products due to alkylation at the N-3 nitrogen atom of the ring system, 3-alkyl-5-amino-substituted tetrazolo[1,5-a][1,3,5]triazin-7(3H)-ones, as well as products due to alkylation at the exocyclic oxygen atom with tetrazole ring opening, 2-amino-substituted 6-alkoxy-4-azido-1,3,5-triazines. Besides that, the product that was alkylated at the ring N-3 nitrogen atom underwent hydrolytic cleavage of the 1,3,5-triazine ring with elimination of the carbonyl functional group and formation of N-(1-alkyl-1H-tetrazol-5-yl)-N'-alkyl- and N-(1-alkyl-1H-tetrazol-5-yl)-N',N'-dialkylguanidines.

Quantum-chemical and NMR study of nitrofuroxanoquinoline cycloaddition

Using DFT/B3LYP and ab initio RHF quantum-chemical calculations in the triple-zeta basis set 6-31++G** the endo and exo cycloaddition mechanism for the interaction of ethyl vinyl ether, trimethylsilyloxybutadiene, or cyclopentadiene with 5-nitro-7,8-furoxanoquinolines was studied in details. Considering that both in solutions and crystals nitrofuroxanoquinoline exists as an inseparable mixture of two N-oxide tautomers, all cycloaddition processes were studied for both of them. The studied mechanisms practically do not depend on the location of the exocyclic oxygen atom in nitrofuroxanoquinoline molecule. At the first step of all reactions the conjugated nitroarene fragments C=C–N=O react with nucleophilic reagents following the mechanism of endo-[4+2] cycloaddition with inverse electronic demand. Further (in the cases of trimethylsilyloxybutadiene and cyclopentadiene) endo-[4+2] cycloadducts recyclize spontaneously according to the mechanism of [3,3] sigmatropic rearrangement into more thermodynamically stable, experimentally detected endo-[2+4] cycloadducts. Both endo-[4+2] and endo-[2+4] cycloadducts obtained from cyclopentadiene and nitrofuroxanoquinoline have been experimentally isolated and characterized. For this case, the kinetic and activation parameters of [4+2] → [2+4] transformation have been studied by 1H NMR method, which have shown an excellent agreement with quantum-chemical results. In all cases the exo processes are one-step reactions, less favorable kinetically than their endo competitors.

Theoretical analysis on the aromaticity of uracil: Important electronic configurations and solvent effect on the aromaticity

Aromaticity and the important electronic configurations of uracil are studied by index of deviation from aromaticity (IDA) and CiLC (CI/LMO/CASSCF) analysis. The calculated IDA values of uracil are 5.256 and 4.998 in gas phase and in solvent model, respectively. These large IDA values indicate that uracil is almost completely non-aromatic even in solvent. The CiLC analysis has revealed that main ionic electronic configurations of uracil involve charge transfer from endocyclic neighboring carbon atom to exocyclic oxygen atom.

An encaged σ∗ orbital in 3-methoxy-2,4,10-trioxaadamantane. Preferred exo-anomeric effect as revealed by the crystal structure

In the titled tricyclic orthocarbonate derivative, the three endocyclic C–O bonds are longer than the exocyclic C–O bond (∼1.40Å vs. ∼1.37Å). This indicates an anomeric-type interaction between the two electron lone pairs on the exocyclic oxygen atom and the antibonding orbitals of the two antiperiplanar endocyclic C–O bonds. The remaining endocyclic C–O bond – marginally shorter than the other two – apparently adds to this effect. Intriguingly, the antibonding orbital of the exocyclic C–O bond extends into the interior of the adamantyl cage, and is stereoelectronically prevented from overlapping with any of the six adjacent lone pairs. The results also seem to indicate a preference for interaction between a single donor oxygen atom and multiple acceptor antibonding orbitals rather than vice versa. The results add insightfully to the substantial body of evidence favouring the antiperiplanar lone pair hypothesis (ALPH).

Inhibition of the Ribonuclease H Activity of HIV-1 Reverse Transcriptase by GSK5750 Correlates with Slow Enzyme-Inhibitor Dissociation

Compounds that efficiently inhibit the ribonuclease (RNase) H activity of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have yet to be developed. Here, we demonstrate that GSK5750, a 1-hydroxy-pyridopyrimidinone analog, binds to the enzyme with an equilibrium dissociation constant (K(d)) of ~400 nM. Inhibition of HIV-1 RNase H is specific, as DNA synthesis is not affected. Moreover, GSK5750 does not inhibit the activity of Escherichia coli RNase H. Order-of-addition experiments show that GSK5750 binds to the free enzyme in an Mg(2+)-dependent fashion. However, as reported for other active site inhibitors, binding of GSK5750 to a preformed enzyme-substrate complex is severely compromised. The bound nucleic acid prevents access to the RNase H active site, which represents a possible biochemical hurdle in the development of potent RNase H inhibitors. Previous studies suggested that formation of a complex with the prototypic RNase H inhibitor β-thujaplicinol is slow, and, once formed, it dissociates rapidly. This unfavorable kinetic behavior can limit the potency of RNase H active site inhibitors. Although the association kinetics of GSK5750 remains slow, our data show that this compound forms a long lasting complex with HIV-1 RT. We conclude that slow dissociation of the inhibitor and HIV-1 RT improves RNase H active site inhibitors and may circumvent the obstacle posed by the inability of these compounds to bind to a preformed enzyme-substrate complex.

Axially chiral pyridine compounds: synthesis, chiral separations and determination of protonation dependent barriers to hindered rotation

Axially chiral enantiomeric 2-pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones have been synthesized and their rotational barriers around the N-3C(pyridyl) bond have been determined by variable temperature NMR or by thermal racemization of the micropreparatively resolved enantiomers. Rotational barriers of the unprotonated compounds ranged from 46 to 116kJ/mol, depending on the substituent on the N-3-pyridyl ring and on the exocyclic oxygen or sulfur atoms of the thiazolidine ring. Protonation of the pyridine nitrogens by TFA caused a decrease in the barrier to the rotation by stabilizing the transition state of the rotations via hydrogen bonding interactions.

Metal complex–DNA binding: Insights from molecular dynamics and DFT/MM calculations

Molecular dynamics (MD) simulations, followed by density functional theory/molecular mechanics (DFT/MM) calculations, provided a detailed structure of the binding site between the cationic metallointercalator (dipyrido [3,2-a:2′,3′-c]phenazine)(glycinato)copper(II), [Cu(gly)(dppz)]+, and the two dodeca-deoxynucleotide duplexes [dodeca(dG-dC)]2 and [dodeca(dA-dT)]2. Three simultaneous DNA binding types were detected in the fully optimized DFT/MM structures: 1) metal coordination through exocyclic oxygen atoms of nitrogen bases; 2) intercalation of the dppz chromophore between stacked Watson–Crick AT–AT and GC–GC bases; and 3) hydrogen bonding between the glycinato ligand and amine groups or heterocyclic nitrogen atoms of DNA bases. Standard enthalpy and Gibbs free energy values were used to evaluate, in vacuo and in solution, the formation energy of both [Cu(gly)(dppz)]/dodecanucleotide complexes. The latter were in excellent agreement with the recently reported value of the experimental DNA-binding constant, providing a physical interpretation of the enthalpy, entropy and solvent contributions in the binding mechanism.