Pseudo Ring Research Articles

Refinement of the Drude Polarizable Force Field for Hexose Monosaccharides: Capturing Ring Conformational Dynamics with Enhanced Accuracy.

We present a revised version of the Drude polarizable carbohydrate force field (FF), focusing on refining the ring and exocyclic torsional parameters for hexopyranose monosaccharides. This refinement addresses the previously observed discrepancies between calculated and experimental NMR 3J coupling values, particularly in describing ring dynamics and exocyclic rotamer populations within major hexose monosaccharides and their anomers. Specifically, α-MAN, β-MAN, α-GLC, β-GLC, α-GAL, β-GAL, α-ALT, β-ALT, α-IDO, and β-IDO were targeted for optimization. The optimization process involved potential energy scans (PES) of the ring and exocyclic dihedral angles computed using quantum mechanical (QM) methods. The target data for the reoptimization included PES of the inner ring dihedrals (C1-C2-C3-C4, C2-C3-C4-C5, C5-O5-C1-C2, C4-C5-O5-C1, O5-C1-C2-C3, C3-C4-C5-O5) and the exocyclic torsions, other than the pseudo ring dihedrals (O1-C1-O5-C5, O2-C2-C1-O5, and O4-C4-C5-O5) and hydroxyl torsions used in the previous parametrization efforts. These parameters, in conjunction with previously developed Drude parameters for hexopyranose monosaccharides, were validated against experimental observations, including NMR data and conformational energetics, in aqueous environments. The resulting polarizable model is shown to be in good agreement with a range of QM data, experimental NMR data, and conformational energetics of monosaccharides in aqueous solutions. This offers a significant improvement of the Drude carbohydrate force field, wherein the refinement enhances the accuracy of accessing the conformational dynamics of carbohydrates in biomolecular simulations.

Characterization, Hirshfeld surface analysis, DFT study and an in vitro α-glucosidase/α-amylase/radical scavenging profiling of novel 5-styryl-2-(4-tolylsulfonamido) chalcones

Sulfonylation of the 5-styryl-2-aminochalcones with p-toluenesulfonyl chloride in pyridine afforded novel 5-styryl-2-sulfonamidochalcone hybrids. XRD analysis of a representative compound helped to confirm the presence of a six-membered N–H···O intramolecularly hydrogen bonded chair-like pseudo ring. Topology was determined through Hirshfeld surface analysis and the energy of frontier molecular orbitals was used to evaluate the stability of this compound. The inhibitory effect of the test compounds against α-glucosidase and α-amylase activities was evaluated in vitro through enzymatic assays, and their antioxidant properties also in vitro through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging assays. An in vitro cell-based antioxidant activity assay of the most active compounds, 2f and 2h, involving lipopolysaccharide (LPS) induced reactive oxygen species (ROS) production also confirmed their capability to scavenge free radicals. Molecular modelling was used to postulate ligand–enzyme interactions and to rationalize the mechanism of antioxidant effect of these compounds.

195Pt and 15N NMR Data in Square Planar Platinum(II) Complexes of the Type [Pt(NH3)aXb]n (Xb = Combination of Halides): “NMR Effective Molecular Radius” of Coordinated Ammonia

By studying a model set of square‐planar [Pt(NH3)aXb]n (a + b = 4; Xb = combination of b halido ligands; n = 2 – b) complexes, we found that their δ(195Pt) NMR chemical shift decreases proportionally to the platinum bonded halido ligands' ionic radii overall sum. This confirms also for these systems, the already observed NMR shielding attributed to pseudo ring currents, circulating around the M–X bond axis. Moreover, the present data show that also the NH3 ligands are characterized by a constant NMR shielding ability toward the central metal. This could be rationalized in term of a “NMR effective molecular radius” of the NH3 ligand, affecting the observed δ(195Pt) as previously found for halido ligands. Interestingly, a δ(15N) decrease is observed in Pt bonded NH3 ligands if the ionic radius of a cis halido ligand is increased. The opposite occurs if the ionic radius of a trans halido ligand is increased. The two contrasting effects stem from both shielding electric ring currents affecting the cis ligands and prevailing trans‐influence due to coordinated halido ligands.

Boron-Based Chiral Helix Be6 B10 2- and Be6 B11 - Clusters: Structures, Chemical Bonding, and Formation Mechanism.

Boron forms a rich variety of low-dimensional nanosystems, including the newly discovered helix Be6 B10 2- (1) and Be6 B11 - (2) clusters. We report herein on the elucidation of chemical bonding in clusters 1/2, using the modern quantum chemistry tools of canonical molecular orbital analyses and adaptive natural density partitioning (AdNDP). It is shown that clusters 1/2 contain a chiral helix Be2 B10 Be2 or Be2 B11 Be2 skeleton with a total of 11 and 12 segments, respectively, which effectively curve into "helical pseudo rings" and chemically consist of two "quasicircles" as defined by their anchoring Be centers. The helix skeleton is connected via Lewis-type B-B and Be-B-Be σ bonds, being further stabilized by island π/σ bonds and a loose π bond at the junction. The Be6 component in 1/2 assumes a distorted prism shape only physically, and it is fragmented into four parts: two terminal Be2 dimers and two isolated Be centers. A Be2 dimer at the far end manages to bend over and cap a quasicircle from one side of B plane. Consequently, each quasicircle of a helical pseudo ring is capped from opposite sides by two Be2 /Be units, facilitating intramolecular charge-transfers of 5 electrons from Be to B. Overall, the folding of B helix involves as many as 10 electrons. The enormous electrostatics offers the ultimate driving forces for B helix formation.

Synthesis, spectroscopic investigation, computational, stereochemical and biological studies of 1,3-dimethyl-2,6-diphenylpiperidin-4-one N(4′)-cyclohexylsemicarbazone: Crystal structure and Hirshfeld surface analysis

Abstract 1,3-Dimethyl-2,6-diphenylpiperidin-4-one N(4′)-cyclohexylsemicarbazone (DDPCS) has been synthesized and characterized by IR, 1H NMR and 13C NMR spectral analysis. IR and NMR spectra of compound DDPCS have been simulated by computational method using DFT-B3LYP with the 6–31 G basis set. Single crystal X-ray diffraction analysis has been performed and it evidences the configuration about C=N double bond is E and the chair conformation of the heterocyclic ring. The N H••••O intermolecular hydrogen bonding in the crystal structure forms an eight membered pseudo ring with the R22 (8), Etter's graph set. The computational, spectral and X-ray structural results exemplifies the chair conformation of the heterocyclic ring with the equatorial orientation of bulky groups. The calculated vibrational frequencies of the normal modes accorded well with the experimental values. Hirshfeld surface analysis was also carried out and discussed in detail. The synthesized compound was screened for its in vitro antimicrobial activity.

Intramolecular single H bonding vs bifurcation in tuning the conformation of 2,2′-dihydroxybenzophenone and its derivatives: a DFT insight

2,2′-dihydroxybenzophenones and their oxime and N-acyl hydrazone derivatives have been studied via the DFT/B3LYP-6-311++G** methodology. An almost coplanar bifurcated six-membered H bridge is found in ketones. A similar H bridge, accompanied by a seven-membered one in oximes and a nine-membered-like one in hydrazones, is also formed. While the closed (two pseudo rings) conformer is the lowest energy one in 2,2′-dihydroxybenzophenones and their oximes, the semi-closed conformer (one pseudo ring) corresponds to the lowest energy one in N-acyl hydrazones. The ΔHf of the closed conformer compared to its open counterpart is ca. 17 kcal/mol in 2,2′-dihydroxybenzophenones while that in oximes is ca. 11 kcal/mol. The energy barrier in changing from the closed to the open (no pseudo ring) conformation is <3 kcal/mol for all 2,2′-dihydroxybenzophenones and their oximes. The impact of intramolecular hydrogen bonding on the variation of ΔHf of the conformers are discussed with respect to mono- and di-p-substitution of 2,2′-dihydroxybenzophenone structure as well as to its conversion into oxime and hydrazone derivatives. ΔHf of both closed and semi-closed conformers decreases, throughout the series, unlike that of semi-closed conformer of the Br-substituted ones. A slightly decreased enthalpy due to intramolecular hydrogen bonding in 2,2′-dihydroxybenzophenones is attributed to p-substitution and a further significant decrease is noted in going from 2,2′-dihydroxybenzophenones to oximes. An enthalpy increase, on the other hand, occurs in moving from oxime to hydrazone, again with the exception of semi-closed conformer of the Br-substituted conformers.

2, 2′‐Dihydroxybenzophenones and Derivatives. Efficient Synthesis and Structure Endoscopy by DFT and NMR. Credentials as Potent Antiinflammatory Agents.

Abstract2,2’‐dihydroxybenzophenones and derivatives have been synthesized directly or by oxidation of their incipiently obtained benzylic alcohols by diverse efficient methods. Oxime and N‐acyl hydrazone derivatives have also been prepared. Their structure profile has been scrutinized by DFT/B3LYP‐6‐311++G** methodology, NMR spectroscopy and dihedral angle grid scan analysis. Energetically favorable conformations pointed to (i) an almost coplanar bifurcated 6‐membered H bridge in ketones, (ii) a single 6‐membered H bridge, accompanied by a 7‐membered H bonding interaction in oximes and (iii) a single 6‐membered H‐bridge in hydrazones. In the latter case, a stable conformation with an additional 9‐membered pseudo ring was also found. Highly deshielded protons in the NMR spectra are in accordance with the theoretically obtained findings on the H‐bonded conformers. Significant anti‐inflammatory activity of the compounds has been found by in vivo tests with their oxime and hydrazone derivatives showing the highest activity, hydrazone 11, in partucular, competing with marketed drugs. In silico docking studies point to the perspective potency of these structures as COX‐1/COX‐2 inhibitors.

PARP1: A Promising Target for the Development of PARP1-based Candidates for Anticancer Intervention

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition, increasing chemosensitization and conferring independent antiproliferation against defective homologous recombination cells, has provided a unique opportunity for anticancer therapeutic intervention. Therefore, PARP1, the best characterized enzyme among PARP family, is presently serving as a well-established target for the treatment of oncology attributed to its intimate role in DNA repair. Nowadays, intensified medicinal chemistry efforts have led to the discovery of 12 PARP1 inhibitors that have been advanced into clinical trial. In this article, we classify these candidates as three categories based on the chemical structure, including lactam type, pseudo ring type and untypical PARP1 inhibitors, for a sequential overview of them. In particular, the development of some candidates will serve the purpose for the future exploration of PARP1 inhibitors.

Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.

The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

PSEUDO BUCHSBAUMNESS FOR IDEALIZATIONS OF NOETHERIAN MODULES OVER LOCAL RINGS

Let (R, 𝔪) be a Noetherian local ring with dim R = d and M an R-module with dim M &lt; d. We prove in this paper that the idealization R ⋉ M of M over R is a pseudo Buchsbaum ring if and only if so is R.

Foldamers of β-peptides: conformational preference of peptides formed by rigid building blocks. The first MI-IR spectra of a triamide nanosystem

To determine local chirality driven conformational preferences of small aminocyclobutane-1-carboxylic acid derivatives, X-(ACBA) n -Y, their matrix-isolation IR spectra were recorded and analyzed. For the very first time model systems of this kind were deposited in a frozen (~10K) noble gas matrix to reduce line width and thus, the recorded sharp vibrational lines were analyzed in details. For cis-(S,R)-1 monomer two "zigzag" conformers composed of either a six or an eight-membered H-bonded pseudo ring was identified. For trans-(S,S)-2 stereoisomer a zigzag of an eight-membered pseudo ring and a helical building unit were determined. Both findings are fully consistent with our computational results, even though the relative conformational ratios were found to vary with respect to measurements. For the dimers (S,R,S,S)-3 and (S,S,S,R)-4 as many as four different cis,trans and three different trans,cis conformers were localized in their matrix-isolation IR (MI-IR) spectra. These foldamers not only agree with the previous computational and NMR results, but also unambiguously show for the first time the presence of a structure made of a cis,trans conformer which links a "zigzag" and a helical foldamer via a bifurcated H-bond. The present work underlines the importance of MI-IR spectroscopy, applied for the first time for triamides to analyze the conformational pool of small biomolecules. We have shown that the local chirality of a β-amino acid can fully control its backbone folding preferences. Unlike proteogenic α-peptides, β- and especially (ACBA) n type oligopeptides could thus be used to rationally design and influence foldamer's structural preferences.

Syntheses, characterization, and crystal structures of two fluorinated gallium phosphates templated by organic amines

Two fluorinated gallium phosphates templated by organic amines, (C4H15N3)[Ga3F2(PO4)3] (1) and [(C2H10N2)(C2H9N2)][Ga3F4(HPO4)4] (2), have been synthesized under hydrothermal and solvothermal conditions, respectively. The compounds were characterized by elemental analyses, FT-IR spectroscopy, and powder X-ray diffraction. Their crystal structures were determined from single-crystal X-ray diffraction. The crystal structure of 1 has a 3-D framework with 10-membered ring channels along the b-axis. The crystal structure of 2 is an infinite 1-D chain structure, further forming a 3-D supramolecular structure with pseudo 10-membered ring channels along the a-axis through O–H ··· O hydrogen bonds. The protonated organic amine cations are located in the inorganic channel and interact with the polyanion framework both electrostatically and via N–H ··· O and N–H ··· F hydrogen bonds.

KDR inhibitor with the intramolecular non-bonded interaction: Conformation–activity relationships of novel indole-3-carboxamide derivatives

We previously reported that compound 1, having a similar conformation to PTK787 (2) by forming a pseudo ring structure with an intramolecular non-bonded S-O interaction, exhibited a potent inhibitory activity against VEGFR2 tyrosine kinase (KDR). Applying the ideas of pseudo ring formations, we have designed three types of novel indole carboxamide derivatives 5-7 with an intramolecular hydrogen bonding or non-bonded S-O interaction. We describe the design and synthesis of 5-7, and also discuss the relationships of their KDR inhibitory activity and conformations that were stabilized by their intramolecular non-bonded interactions.

Amorphous IGZO TFTs and Circuits on Highly Flexible and Dimensionally Stable Kovar (Ni-Fe alloy) Metal Foils

ABSTRACTWe have fabricated high performance amorphous IGZO TFTs and integrated circuits on flexible kovar (Ni-Fe 42 alloy) foils. Excellent dimensional stability on kovar foils is obtained by a pre-anneal process at 800°C that limits the thermal run-out to within 100ppm. After substrate annealing, Ni-Fe 42 alloy retains high yield strength and good flexibility with the re-crystallized structure containing large isotropic grains between 20-50μm. Amorphous IGZO TFTs and circuits with a staggered, bottom-gate architecture are fabricated and tested. Non-flexed TFTs have field effect mobility of 12 cm2/V.s, threshold voltage around 2 V and sub-threshold swing of 0.6 V/decade and ON/OFF current ratio exceeding 107. Under prolonged uniaxial tensile strain upto 0.8%, TFTs exhibited minimal change in performance which augers well for use of Ni-Fe foil as flexible substrates. To demonstrate the viability of oxide-based device integration, n-type pseudo logic ring oscillator circuits are also evaluated. Sub 300 ns propagation delay is confirmed at a rail-rail supply voltage of 40 V. The results suggest that device integration on such a highly flexible substrate is amenable to roll-to-roll processing of future electronics.

Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors

Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.

Synthesis, spectral and RAHB studies on some arylhydrazones of β-diketones: crystal and molecular structures of 2-(2-(3-pyridyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 2-(2-(2-methoxyphenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione

The present study describes the synthesis and spectral analysis of a series of arylhydrazones of β-diketones (1–6) along with the single crystal X-ray structural studies of 2-(2-(3-pyridyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione (3) and 2-(2-(2-methoxyphenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione (6). Spectral and structural studies clearly exemplify the effective intramolecular hydrogen bonding and as a result the NH proton signals and carbonyl carbon signals are shifted to higher frequency region in NMR spectra. Structural implications imposed by the formation of pseudo six-membered ring after hydrogen bonding is well observed in XRD analysis. XRD analysis also evidences the envelop conformation of the dimedone ring in both the cases and resonance assisted hydrogen bonding (RAHB) studies were also performed.

ChemInform Abstract: Entry into a New Class of Protein Kinase Inhibitors by Pseudo Ring Design.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dietary Polyphenols as Topoisomerase II Poisons: B Ring and C Ring Substituents Determine the Mechanism of Enzyme-Mediated DNA Cleavage Enhancement

Dietary polyphenols are a diverse and complex group of compounds that are linked to human health. Many of their effects have been attributed to the ability to poison (i.e., enhance DNA cleavage by) topoisomerase II. Polyphenols act against the enzyme by at least two different mechanisms. Some compounds are traditional, redox-independent topoisomerase II poisons, interacting with the enzyme in a noncovalent manner. Conversely, others enhance DNA cleavage in a redox-dependent manner that requires covalent adduction to topoisomerase II. Unfortunately, the structural elements that dictate the mechanism by which polyphenols poison topoisomerase II have not been identified. To resolve this issue, the activities of two classes of polyphenols against human topoisomerase IIalpha were examined. The first class was a catechin series, including (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC). The second was a flavonol series, including myricetin, quercetin, and kaempferol. Compounds were categorized into four distinct groups: EGCG and EGC were redox-dependent topoisomerase II poisons, kaempferol and quercetin were traditional poisons, myricetin utilized both mechanisms, and ECG and EC displayed no significant activity. On the basis of these findings, a set of rules is proposed that predicts the mechanism of bioflavonoid action against topoisomerase II. The first rule centers on the B ring. While the C4'-OH is critical for the compound to act as a traditional poison, the addition of -OH groups at C3' and C5' increases the redox activity of the B ring and allows the compound to act as a redox-dependent poison. The second rule centers on the C ring. The structure of the C ring in the flavonols is aromatic and planar and includes a C4-keto group that allows the formation of a proposed pseudo ring with the C5-OH. Disruption of these elements abrogates enzyme binding and precludes the ability to function as a traditional topoisomerase II poison.

Entry into a new class of protein kinase inhibitors by pseudo ring design

A pyrimidin-4-yl-urea motif forming a pseudo ring by intramolecular hydrogen bonding has been designed to mimic the pyrido[2,3-d]pyrimidin-7-one core structure of a well-established class of protein kinase inhibitors. Potent inhibition of a number of protein kinases was obtained with the first prototype compound synthesized to probe the design concept.

N–H…O intramolecular hydrogen bonds – The influence of external agents on π-electron delocalization

N–H…O and O–H…N intramolecular hydrogen bonds are analyzed theoretically at MP2/6-311++G(d,p) level of approximation. The influence of the external agents: Li +, Na +, HF and HCl Lewis acids, on the pseudo ring of conjugated single and double bonds closed by hydrogen bond is investigated. These external agents are responsible for the enhancement of π-electron delocalization and the equalization of conjugated bonds but it does not correspond to the strengthening of hydrogen bonding. The Bader theory is also applied to indicate and to analyze critical points. The characteristics of bond and ring critical points are determined to deepen the nature of π-electron delocalization and of hydrogen bond interaction.