Substitution Pattern Of Ring Research Articles

Synthesis of Benzoacridines and Benzophenanthridines by Regioselective Pd‐Catalyzed Cross‐Coupling Reactions Followed by Acid‐Mediated Cycloisomerizations

A convenient synthesis of various benzoacridines and benzophenanthridines from readily available dihalogenated quinolines is reported. The synthesis is based on regioselective Suzuki and Sonogashira reactions followed by Brønsted acid‐mediated cycloisomerization. The developed methodology is highly modular and allows the construction of various ring systems and substitution patterns in high yields. The optical and electrochemical properties of selected derivatives were investigated.

Ditocopheryl Sulfides and Disulfides: Synthesis and Antioxidant Profile.

Symmetrical ditocopheryl disulfides (Toc)2 S2 and symmetrical and unsymmetrical ditocopheryl sulfides (Toc)2 S were simply prepared under remarkably mild conditions with complete control of the regiochemistry by using δ-, γ-, and β-tocopheryl-N-thiophthalimides (Toc-NSPht) as common starting materials. The roles of sulfur atom(s), H-bond and aryl ring substitution pattern on the antioxidant profile of these new compounds, which were assembled by linking together two tocopheryl units, are also discussed.

A Review on Daphnane-Type Diterpenoids and Their Bioactive Studies.

Natural daphnane diterpenoids, mainly distributed in plants of the Thymelaeaceae and Euphorbiaceae families, usually include a 5/7/6-tricyclic ring system with poly-hydroxyl groups located at C-3, C-4, C-5, C-9, C-13, C-14, or C-20, while some special types have a characteristic orthoester motif triaxially connectedat C-9, C-13, and C-14. The daphnane-type diterpenoids can be classified into five types: 6-epoxy daphnane diterpenoids, resiniferonoids, genkwanines, 1-alkyldaphnanes and rediocides, based on the oxygen-containing functions at rings B and C, as well as the substitution pattern of ring A. Up to now, nearly 200 daphnane-type diterpenoids have been isolated and elucidated from the Thymelaeaceae and Euphorbiaceae families. In-vitro and in-vivo experiments of these compounds have shown that they possess a wide range of biological activities, including anti-HIV, anti-cancer, anti-leukemic, neurotrophic, pesticidal and cytotoxic effects. A comprehensive account of the structural diversity is given in this review, along with the cytotoxic activities of daphnane-type diterpenoids, up to April 2019.

Vanadyl Porphyrin Speciation Based on Submegahertz Ligand Proton Hyperfine Couplings

The speciation of vanadyl (VO2+) porphyrins in crude oil (vanadyl petroporphyrins) is an area of ongoing interest in petroleomics. In this paper, we describe a method for the speciation of vanadyl porphyrins that uses electron nuclear double resonance (ENDOR), a high-resolution electron paramagnetic resonance (EPR) spectroscopic technique. We use 1H ENDOR to measure hyperfine couplings between ligand protons and the paramagnetic vanadyl ion as small as about 0.15 MHz. From the measured hyperfine couplings, we directly determine all vanadium–ligand proton distances up to 8 A. This information differentiates porphyrin ligands by their ring substitution pattern and substituent nature. We demonstrate this using a series of vanadyl porphyrin model compounds. Additionally, we demonstrate that the composition of binary vanadyl porphyrins mixtures can be determined. The ability of ENDOR to differentiate types of ligand protons in vanadyl porphyrin mixtures provides a basis for analyzing more complex mixtures of v...

Synthesis of photocaged diamines and their application in photoinduced self‐assembly

AbstractThe photochemical cleavage of covalent bonds is an important strategy in protection group chemistry, as well as for the triggering of chemical events posterior to the application of the physicochemical stimulus. Photocages allow the arresting and traceless liberation of a chemical entity, which can be broadly applied as a functional control element in materials chemistry and the life sciences in general. Among the best studied and most versatile light‐sensitive protecting groups known to date rank the o‐nitrobenzyl derivatives, entities which are easily introduced to amines, thiols, and alcohols. Their photolability relies on a phototautomerisation‐induced cleavage mechanism, a phenomenon largely dependent on the substitution pattern of the aromatic ring in the o‐nitrophenyl‐moiety. Although well described and studied in detail for the protection of amino groups of different nature, the photocaging of aliphatic diamines has not been described in detail to date. Because of their interesting properties as synthons in supramolecular and polymer chemistry alike, we wish to describe the efficient photocaging of diamines with o‐nitrobenzyl derivatives, their photocleavage behavior over time, as well as their application in a photoinduced templated self‐assembly reaction towards cyclic imines.

Encoding of Promiscuity in an Aminoglycoside Acetyltransferase.

Aminoglycoside antibiotics are a large family of antibiotics that can be divided into two distinct classes on the basis of the substitution pattern of the central deoxystreptamine ring. Although aminoglycosides are chemically, structurally, and topologically diverse, some aminoglycoside-modifying enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides from the two main classes, the kanamycin- and neomycin-based antibiotics. Here, we present the crystal structure of a promiscuous AGME, aminoglycoside- N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A (CoASH) complexes, and in the ternary neomycin-CoASH complex. These data provide a structural framework for interpretation of the thermodynamics of enzyme-ligand interactions and the role of solvent in the recognition of ligands. In combination with the recent structure of an AGME that does not have broad substrate specificity, these structures allow for the direct determination of how antibiotic promiscuity is encoded in some AGMEs.

Volatiles from the xylarialean fungus Hypoxylon invadens.

The volatiles emitted by agar plate cultures of the xylarialean fungus Hypoxylon invadens were investigated by use of a closed loop stripping apparatus in combination with GC–MS. Several aromatic compounds were found that could only be identified by comparison to all possible constitutional isomers with different ring substitution patterns. For the set of identified compounds a plausible biosynthetic scheme was suggested that gives further support for the assigned structures.

Synthesis, Photophysical and Electrochemical Properties of Novel D-π-D and D-π-A Triphenylamino-Chalcones and β-Arylchalcones

A series of triphenylamino (TPA)-chalcones and triphenylamino-β-arylchalcones, displaying either D-π-D or D-π-A architecture, were synthesized through aldol condensations and Heck reactions. The chalcone derivatives display intense absorption bands ranging from 389 to 432 nm and molar extinction coefficients of ca. 105 L mol-1 cm-1 corresponding to π-π* electronic transitions. The photoluminescence emissions are peaked between 470 and 563 nm with large Stokes shifts (80-131 nm), attributed to charge transfer in the excited state. The dyes present low fluorescence quantum yields, which is attributed to radiationless excited state deactivation related to aryl rings rotation. Spectroscopic and electrochemical methods were used to determine the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels. Both optical and electrochemical properties of the TPA-chalcone derivatives are considerably affected by the substitution pattern of the chalcones aryl rings and also by the β-arylation of the olefin moiety.

Structure-Function Relationship Studies In Vitro Reveal Distinct and Specific Effects of Long-Chain Metabolites of Vitamin E.

Cytochrome-dependent metabolism of vitamin E initially forms the long-chain metabolites (LCM) 13'-hydroxychromanols (13'-OH) and 13'-carboxychromanols (13'-COOH), which occur in human blood. Little is known about their biological functions. A structure-activity relationship study using α- and δ-tocopherol (TOH), their LCM (α-13'-OH, δ-13'-OH, α-13'-COOH, and δ-13'-COOH) and representatives of their substructures (α-carboxyethylhydroxychromanol and pristanic acid) is performed to unravel critical structural elements of the LCM for biological activity. Prominent effects are mediated by α- and δ-LCM, as scavenger receptor cluster of differentiation 36 (CD36) expression is induced in human THP-1 macrophages and lipopolysaccharide-stimulated inducible nitric oxide synthase (iNos) expression is inhibited in murine RAW264.7 macrophages, while the other molecules are less or not effective. The LCM effects depend on the presence of the chromanol ring system and on the modification of the side-chain but not on the substitution pattern of the chromanol ring. Therefore, it can be concluded that for mediation of effects by LCM the entire molecule is needed and that the effects are specific. We propose the LCM of the micronutrient vitamin E as a new class of regulatory metabolites, but further studies are needed to corroborate this hypothesis.

Topliss Batchwise Schemes Reviewed in the Era of Open Data Reveal Significant Differences between Enzymes and Membrane Receptors.

In 1977, John G. Topliss introduced the Topliss Batchwise Scheme, a straightforward nonmathematical procedure to assist medicinal chemists in optimizing the substitution pattern of a phenyl ring. Despite its long period of application, a thorough validation of this method has been missing so far. Here, we address this issue by gathering 129 congeneric series from the ChEMBL database, suitable to retrospectively assess the approach. Frequency analysis of Topliss' schemes showed that the π, Es, σ, and -σ scheme occurred in 17, 20, 6, and 4 congeneric series, respectively. We observed a significant difference of π scheme frequency in enzymes versus membrane receptors, with 12 versus only 2 occurrences. Validation of Topliss schemes in potency optimization showed a remarkable performance increase after restricting the data set to analogue series tested solely against enzymes. In this setting, the Es and the π scheme were successful in 50% and 56% of the analogue series, respectively.

Differentiation of the six dimethoxypyrovalerone regioisomers: GC-MS, GC-MS/MS and GC-IR

Multiple and complementary analytical methods are often necessary for the identification of a specific compound from a series of closely related structural isomers. Gas chromatography-mass spectrometry (GC-MS), gas chromatography-product ion mass spectrometry (GC-MS/MS) and gas chromatography-infrared spectroscopy (GC-IR) were used to differentiate between the six dimethoxypyrrovalerone (DMPV) regioisomers. The six regioisomeric aminoketones were separated on a 50% phenyl stationary phase and the elution order is related to the positioning of substituents on the aromatic ring. These six DMPV regioisomers yield essentially identical mass spectral data in both chemical ionization (CI-MS) and electron ionization (EI-MS) spectra as well as identical product ion MS/MS spectra of the iminium cation base peak (m/z 126). These various mass spectral techniques provide data to identify all major structural features of these molecules except the dimethoxy substitution pattern of the aromatic ring. The region of the vapor phase infrared spectra between 1600cm−1 and 1000cm−1 provides a significant number of unique absorption bands characteristic of each individual DMPV regioisomer.

Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection.

A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure−activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4–28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure−activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly.

Positional Isomerism and Steric Effects in the Self-Assemblies of Phenylene Bis-Monothiooxalamides

The potential interplay of steric and substitution pattern effects of the monothiooxalamide side arms on the structure, conformational features, and self-assembly of a series of phenylene bis-monothiooxalamides was investigated. Herein we have demonstrated that phenylene bis-monothiooxalamides self-associate in the solid state, through intermolecular hydrogen bonding as meso-helices when the thioamide NR group is sBu and through dispersive CO···CX (X = O, S, π), S···S, and C–H···S interactions when R is tBu, independently from the substitution pattern in the phenyl ring. The helical structures are exclusively developed through NCSH···O hydrogen bonding. The steric strain imposed by the ortho-substitution pattern has the effect of moving both monothiooxalyl units out of the phenyl plane enabling dimerization through strong NCOH···O intermolecular hydrogen bonds and promotes the formation of meso-helices. The steric demand of the thioamide NR group rules the conformation adopted by meta-substituted derivati...

Copper and Gold Cyclic (Alkyl)(amino)carbene Complexes with Sub-Microsecond Photoemissions: Structure and Substituent Effects on Redox and Luminescent Properties.

Copper and gold halide and pseudo-halide complexes stabilised by methyl-, ethyl- and adamantyl-substituted cyclic (alkyl)(amino)carbene (CAAC) ligands are mostly linear monomers in the solid state, without aurophilic Au⋅⋅⋅Au interactions. (Et2 L)CuCl shows the highest photoluminescence quantum yield (PLQY) in the series, 70 %. The photoemissions of Me2 L and Et2 L copper halide complexes show S1 →S0 fluorescence on the ns time scale, in agreement with theory, as well as a long-lived emission. Monomeric (Me2 L)CuNCS is a white emitter, whereas dimeric [(Et2 L)Cu(μ-NCS)]2 shows intense yellow emission with a photoluminescence (PL) quantum yield of 49 %. The reaction of (Ad L)MCl (M=Cu or Au) with phenols ArOH (Ar=Ph, 2,6-F2 C6 H3 , 2,6-Me2 C6 H3 , 3,5-tBu2 C6 H3 , 2-tBu-5-MeC6 H3 , 2-pyridyl), thiophenol, or aromatic amines H2 NAr'' (Ar'=Ph, 3,5-(CF3 )2 C6 H3 , C6 F5 , 2-py) afforded the corresponding phenolato, thiophenolato and amido complexes. Although the emission wavelengths are only marginally affected by the ring substitution pattern, the PL intensities respond sensitively to the presence of substituents in the ortho or meta positions. In gold aryloxides, PL is controlled by steric factors, with strong luminescence in compounds with Au-O-C-C torsion angles <50°. Calculations confirm the dependence of oscillator strength on the torsion angle, as well as the inter-ligand charge transfer nature of the emission. The HOMO/LUMO energy levels were estimated based on first reduction and oxidation potentials.

Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells

We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future clinical candidates.

Synthesis and anti-inflammatory activity of isoquebecol

We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor, followed by a double Suzuki-Miyaura reaction. The anti-inflammatory activity of isoquebecol was studied on macrophage cells by monitoring its ability to inhibit LPS-induced IL-6 secretion. Results show that this new compound has an improved bioactivity over that of its natural isomer. Precursors and derivatives of quebecol, isoquebecol and model analog 2,3,3-triphenylpropanol were also prepared and tested in this study. Comparison between the three series of compounds led to establishing new SARs concerning the aryl ring substitution pattern on the triarylpropanol scaffold and substructure functionalization.

GC–MS, GC–MS/MS and GC-IR differentiation of carbonyl modified analogues of MDPV

A combination of GC–MS, GC–MS/MS and GC-IR techniques can be used to differentiate 2,3- and 3,4-MDPV from the carbonyl modified analogues, aminoalcohols and the corresponding desoxy substituted phenethylamines. These six compounds all yield the identical base peak iminium cation at m/z 126 in their electron ionization mass spectrum. The MS/MS evaluation of the iminium cation fragment yields identical major product ions at m/z 84. Soft ionization via methanol CI-MS confirms the molecular weight for all these compounds. The only peak in the CI-MS for the aminoketones and the desoxy substituted phenethylamines occurs at (M+H)+. The aminoalcohols show a characteristic fragment ion in CI-MS corresponding to the loss of H2O from the (M+H)+. Vapor phase infrared spectra (GC-IR) confirm the aromatic ring substitution pattern via unique absorption in the 1450cm−1 range. In all GC separations the 2,3-methylenedioxy substituted isomer elutes before the analogous 3,4-isomer.

Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5 negative allosteric modulation

Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences.

ChemInform Abstract: Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry ‐ Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

AbstractReview: [56 refs.

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

AbstractRecent advances in the field of ring‐expansion chemistry, involving 1‐azoniabicyclo[n.1.0]alkane scaffolds (bicyclic aziridinium ions) as key transient intermediates, have made it possible to efficiently construct a broad variety of medium‐ and large‐sized functionalized nitrogen‐containing heterocycles. In this tutorial review, a comprehensive survey of all pathways leading to the generation of 1‐azoniabicyclo[n.1.0]alkanes is provided, as well as a discussion on their subsequent ring expansions to relevant azaheterocycles governed by ring size, substitution pattern, and/or nature of applied nucleophiles.magnified image