Ring Analogues Research Articles

The evaluation of N-propargylamine-2-aminotetralin as an inhibitor of monoamine oxidase

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson’s disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson’s disease and depression.

Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies.

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.

Finite Σ-Rickart modules

After hereditary rings were defined, as a natural generalization, semi-hereditary rings were introduced. In this article, we study the notion of a finite Σ-Rickart module, as a module theoretic analogue of a right semi-hereditary ring. A module M is called finite Σ-Rickart if every finite direct sum of copies of M is a Rickart module. It is shown that any direct summand and any finite direct sum of copies of a finite Σ-Rickart module are finite Σ-Rickart modules. We also provide generalizations in a module theoretic setting of the most common results of semi-hereditary rings: a ring R is right semi-hereditary if and only if every finitely generated submodule of any projective right R-module is projective if and only if every factor module of any injective right R-module is f-injective. Further, we have a characterization of a finite Σ-Rickart module in terms of its endomorphism ring. In addition, we introduce M-coherent modules and provide a characterization of a finite Σ-Rickart module in terms of an M-coherent module. We prove that for any endoregular module M, is an f-injective right S-module for any module A, where Examples which delineate the concepts and results are provided.

Secondary-sphere modification in proline catalysis: old friend, new connection.

In this work, we exploit our strategy of in situ secondary-sphere modification of organocatalysts to improve the reactivity and selectivity of amino catalysts. Herein, the carboxylic acid moiety of proline was targeted as a site for modification under catalytic reaction conditions with boronic acids. Intermolecular aldol reactions between aromatic aldehydes and cyclopentanone were selected as a proof-of-concept because cyclopentanone as an aldol donor was often associated with decreased selectivity compared to its 6-membered ring analog, hexanone. Our secondary-sphere modification strategy, using naturally occurring L-proline amino acid, enabled reactions at room temperature with high levels of diastereo- and enantio-selectivity and short reaction times. NMR and HR-MS studies shed light on the nature of the catalyst structure and on the role of water in our reactions.

Synthesis and analytical differentiation of a novel synthetic cathinone 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidin-1-yl)butan-1-one (5-PPDI) and its regioisomers

The differentiation of a controlled drug from uncontrolled novel compounds related to regioisomers is a significant issue in forensics. The compound 1-(2,3-dihydro-1H-inden-5-yl)-2-(pyrrolidin-1-yl)butan-1-one (5-PPDI) is a novel synthetic cathinone first identified in 2015 as a new psychoactive substance. 5-PPDI is the indanyl analog of α-PBP, a typical synthetic cathinone, as well as the aliphatic ring analog of MDPBP, a synthetic cathinone with a heterocyclic ring. 5-PPDI can have three possible regioisomers, 1-(2,3-dihydro-1H-inden-1-yl)-2-(pyrrolidin-1-yl)butan-1-one (1-PPDI), 1-(2,3-dihydro-1H-inden-2-yl)-2-(pyrrolidin-1-yl)butan-1-one (2-PPDI), and 1-(2,3-dihydro-1H-inden-4-yl)-2-(pyrrolidin-1-yl)butan-1-one (4-PPDI), differing by the substituted position of the alkyl side-chain. In this study, 5-PPDI and its three regioisomers were synthesized from commercially available precursor compounds and analyzed by gas chromatography/electron ionization–quadrupole mass spectrometry (GC/EI–Q-MS) and by liquid chromatography/electrospray ionization–linear ion trap mass spectrometry (LC/ESI–LIT–MS). The four PPDI isomers could be differentiated by GC/EI–Q-MS with three types of separation columns and by 2nd generation product ion spectra (MS3) analysis using ESI–LIT–MS.

Mechanistic Insights into the Organocatalytic Kinetic Resolution of Oxazinones through Alcoholysis

AbstractA complete computational study has been performed in order to rationalise the results of a new organocatalytic approach to the kinetic resolution of 4‐substituted oxazinones which results in highly enantioenriched and orthogonally‐protected β‐amino acids. DFT‐analysis elucidated the preferable binding orientation of the 4‐oxazinone under study, predicted the formation of the observed major R product with a calculated ee in good agreement with the experimental data and allowed a complete mechanistic and stereochemical understanding of the catalysis. The alcoholytic kinetic resolution of a 7‐memebered ring analogue to generate enantioenriched γ‐amino acids was experimentally and computationally investigated for the first time.

Magic Rings: Navigation in the Ring Chemical Space Guided by the Bioactive Rings

The large majority of bioactive molecules contain a more or less complex ring system as a central structural element. This central core determines the basic molecule shape, keeps substituents in their proper positions, and often also contributes to the biological activity itself. In this study the ring systems extracted from one billion molecules are processed and differences between rings from bioactive molecules and common synthetic molecules are analyzed. The bioactive rings seem to be distributed throughout the large portion of chemical space, but not uniformly; one can see several more dense regions, where the bioactive rings often appear in small clusters, as well as empty areas. A web tool offering an interactive navigation in the ring chemical space and supporting identification of bioisosteric ring analogs available at https://bit.ly/magicrings is also described.

A note on a Griffiths-type ring for complete intersections in Grassmannians

We calculate a Griffiths-type ring for smooth complete intersections in Grassmannians. This is the analogue of the classical Jacobian ring for complete intersections in projective space and allows us to explicitly compute their Hodge groups.

Synthesis of [6-6-6] ABE tricyclic ring analogues of methyllycaconitine

A new synthesis of the bridged [6-6-6] ABE tricyclic ring analogues of methyllycaconitine with the C-1 oxygenated substituents has been developed using an efficient aza-annulation of β-enamino ketone followed by a facile decarboxylation to form BE rings. Subsequent elaboration to form the A ring was achieved by a transannular acyl radical cyclization with concomitant equipment of the key C-1 oxygen functionality.

Synthesis and biological evaluation of a ring analogs of the selective CB2 inverse agonist SMM-189

Microglia are the principle cell type driving sustained neuroinflammation in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Multiple Sclerosis. Interestingly, microglia locked into a chronic M1 pro-inflammatory phenotype significantly up-regulate the cannabinoid receptor 2 (CB2) expression. Our approach to exploiting CB2 as a therapeutic target in neuroinflammatory diseases focuses on the development of selective CB2 inverse agonists to shift microglia bias to a M2 pro-wound healing phenotype. Herein we report work designed to refine the structure activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone CB2 inverse agonist scaffold. A series of analogs of our lead compound SMM-189 were synthesized and measured for affinity/selectivity, potency, and efficacy in regulating cAMP production and β-arrestin recruitment. In this series compound 40 demonstrated a significant increase in potency and efficacy for cAMP stimulation compared to SMM-189. Akin to our lead SMM-189, this compound was highly efficacious in biasing microglia to an M2 pro-wound healing phenotype in LPS stimulated cell lines. These results advance our understanding of the structure–activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold and provide further support for regulating microglia activation using CB2 inverse agonists.

Towards a Ring Analogue of the Leftover Hash Lemma

Abstract The leftover hash lemma (LHL) is used in the analysis of various lattice-based cryptosystems, such as the Regev and Dual-Regev encryption schemes as well as their leakage-resilient counterparts. The LHL does not hold in the ring setting, when the ring is far from a field, which is typical for efficient cryptosystems. Lyubashevsky et al. (Eurocrypt ’13) proved a “regularity lemma,” which can be used instead of the LHL, but applies only for Gaussian inputs. This is in contrast to the LHL, which applies when the input is drawn from any high min-entropy distribution. Our work presents an approach for generalizing the “regularity lemma” of Lyubashevsky et al. to certain conditional distributions. We assume the input was sampled from a discrete Gaussian distribution and consider the induced distribution, given side-channel leakage on the input. We present three instantiations of our approach, proving that the regularity lemma holds for three natural conditional distributions.

Stiff-Stilbene Photoswitches: From Fundamental Studies to Emergent Applications.

Stiff‐stilbene, a sterically restricted fused ring analogue of stilbene, has been regularly used as a model compound in theoretical studies of stilbene photoisomerization. Lately, owing to its excellent photoswitching properties, it is increasingly being applied to reversibly control the properties and function of chemical as well as biological systems. Stiff‐stilbene photoswitches possess a number of advantageous properties including a high quantum yield for photoisomerization and a high thermal stability. Furthermore, they undergo a large geometrical change upon isomerization and their synthesis is straightforward. Herein, we provide an overview of the basic properties of stiff‐stilbene and of recent applications in supramolecular chemistry, catalysis, and biological systems.

Stiff‐Stilbene Photoswitches: From Fundamental Studies to Emergent Applications

AbstractStiff‐stilbene, a sterically restricted fused ring analogue of stilbene, has been regularly used as a model compound in theoretical studies of stilbene photoisomerization. Lately, owing to its excellent photoswitching properties, it is increasingly being applied to reversibly control the properties and function of chemical as well as biological systems. Stiff‐stilbene photoswitches possess a number of advantageous properties including a high quantum yield for photoisomerization and a high thermal stability. Furthermore, they undergo a large geometrical change upon isomerization and their synthesis is straightforward. Herein, we provide an overview of the basic properties of stiff‐stilbene and of recent applications in supramolecular chemistry, catalysis, and biological systems.

Comaximal factorization in a commutative Bezout ring

We study an analogue of unique factorization rings in the case of an elementary divisor domain.

Preparation of Non-Planar-Ring Epoxy Thermosets Combining Ultra-Strong Shape Memory Effects and High Performance

Non-planar-ring epoxies together with non-planar-ring hardeners could achieve thermosets combining ultra-high shape recovery speed and excellent thermal properties. High shape recovery speed reflected high efficiency, and could decrease the energy consumption and the harmful effect of external stimuli on the materials, while it often conflicts with the thermal properties of shape memory polymers. In this paper, for the first time, epoxy resins with the super-short shape recovery time within 3 s were developed from non-planar-ring epoxies and hardeners, and their glass transition temperature (Tg) were ~127 °C much higher than their benzene ring analogues. The effects of non-planar-ring structures of the epoxies and hardeners on the curing behavior, thermal properties as well as the shape memory properties of the thermosets were systematically investigated; the structure-property relationships were disclosed with the help of computational simulation of structure parameters and ESP maps. The faster shape recovery speed of the non-planar-ring epoxy thermosets is from their higher molecular mobility contributed by the conformational transition of non-planar-rings as well as their higher recovery force compared with benzene ring analogs. Their higher Tgs are from the steric hindrance by the larger molecular volume of the non-planar-rings than benzene ring. This work will provide an effective method to produce shape memory polymers with excellent shape memory effects and high performance.

Σ-Rickart modules

Hereditary rings have been extensively investigated in the literature after Kaplansky introduced them in the earliest 50’s. In this paper, we study the notion of a [Formula: see text]-Rickart module by utilizing the endomorphism ring of a module and using the recent notion of a Rickart module, as a module theoretic analogue of a right hereditary ring. A module [Formula: see text] is called [Formula: see text]-Rickart if every direct sum of copies of [Formula: see text] is Rickart. It is shown that any direct summand and any direct sum of copies of a [Formula: see text]-Rickart module are [Formula: see text]-Rickart modules. We also provide generalizations in a module theoretic setting of the most common results of hereditary rings: a ring [Formula: see text] is right hereditary if and only if every submodule of any projective right [Formula: see text]-module is projective if and only if every factor module of any injective right [Formula: see text]-module is injective. Also, we have a characterization of a finitely generated [Formula: see text]-Rickart module in terms of its endomorphism ring. Examples which delineate the concepts and results are provided.

Quantitative Structure-Activity Relationship and Docking Studies on a series of H+/K+-ATPase inhibitors

Background: The Gastric H+/K+-ATPase is also known as proton pump is the enzyme responsible for the acidification of gastric juice. H+/K+ GastroEsophageal Reflux Disease (GERD) and other acid related diseases mainly depend on the inhibition of the gastric H+/K+- ATPase which will finally result in acid secretion in stomach. GERD is one of the diseases that have significant effect on the quality of human life and are the major burden on health care systems is that leads to heart burn, acid regurgitation, chest pain, epigastric pain, and respiratory conditions such as chronic cough. Hence the study of the inhibitors of Gastric H+/K+-ATPase is desired. Methods: Research and online content related to imidazo [1, 2-a]pyrazine and heterocyclic ring analogues (I) that were synthesized and evaluated for their Gastric H+/K+-ATPase inhibitory activity is reviewed, and in order to design and develop still better and more effective H+/K+-ATPase inhibitors, we have made Quantitative Structure Activity Relationship (QSAR), docking and ADMET studies on these compounds. Results: The best MLR equation based on four descriptors along with statistical parameters is obtained using Statistica dataminer software. Using the model expressed by this study we predicted some new compounds of high H+/K+-ATPase inhibition potency. Each predicted compound has very high potency with which only a few compounds of existing series can match. Conclusion: The QSAR and molecular modelling studies suggested that still better compounds can be designed if the flexibility of the molecules can be increased for which attempts can be made to have more saturated atoms in the molecules. Such a compound predicted by us was found to have interactions with the enzyme H+/K+-ATPase almost in the same manner as the FDA approved compounds, lansoprazole, pantaprazole.

Molecular Recognition of Lipid II by Lantibiotics: Synthesis and Conformational Studies of Analogues of Nisin and Mutacin Rings A and B.

In response to the growing threat posed by antibiotic-resistant bacterial strains, extensive research is currently focused on developing antimicrobial agents that target lipid II, a vital precursor in the biosynthesis of bacterial cell walls. The lantibiotic nisin and related peptides display unique and highly selective binding to lipid II. A key feature of the nisin–lipid II interaction is the formation of a cage-like complex between the pyrophosphate moiety of lipid II and the two thioether-bridged rings, rings A and B, at the N-terminus of nisin. To understand the important structural factors underlying this highly selective molecular recognition, we have used solid-phase peptide synthesis to prepare individual ring A and B structures from nisin, the related lantibiotic mutacin, and synthetic analogues. Through NMR studies of these rings, we have demonstrated that ring A is preorganized to adopt the correct conformation for binding lipid II in solution and that individual amino acid substitutions in ring A have little effect on the conformation. We have also analyzed the turn structures adopted by these thioether-bridged peptides and show that they do not adopt the tight α-turn or β-turn structures typically found in proteins.

Resonant inelastic X-ray scattering of a Ru photosensitizer: Insights from individual ligands to the electronic structure of the complete molecule.

N 1s Resonant Inelastic X-ray Scattering (RIXS) was used to probe the molecular electronic structure of the ruthenium photosensitizer complex cis-bis(isothiocyanato) bis(2,2'-bipyridyl-4,4'-dicarboxylato) ruthenium(II), known as "N3." In order to interpret these data, crystalline powder samples of the bipyridine-dicarboxylic acid ligand ("bi-isonicotinic acid") and the single ring analog "isonicotinic acid" were studied separately using the same method. Clear evidence for intermolecular hydrogen bonding is observed for each of these crystalline powders, along with clear vibronic coupling features. For bi-isonicotinic acid, these results are compared to those of a physisorbed multilayer, where no hydrogen bonding is observed. The RIXS of the "N3" dye, again prepared as a bulk powder sample, is interpreted in terms of the orbital contributions of the bi-isonicotinic acid and thiocyanate ligands by considering the two different nitrogen species. This allows direct comparison with the isolated ligand molecules where we highlight the impact of the central Ru atom on the electronic structure of the ligand. Further interpretation is provided through complementary resonant photoemission spectroscopy and density functional theory calculations. This combination of techniques allows us to confirm the localization and relative coupling of the frontier orbitals and associated vibrational losses.

Free extensions and Lefschetz properties, with an application to rings of relative coinvariants

Graded Artinian algebras can be regarded as algebraic analogues of cohomology rings (in even degrees) of compact topological manifolds. In this analogy, a free extension of a base ring with a fibre ring corresponds to a fibre bundle over a manifold. If the manifold is Kähler, then its cohomology ring satisfies the strong Lefschetz property, which means multiplication by a linear form has the largest possible Jordan type. In this paper, we study the behaviour of strong Lefschetz and Jordan type with respect to free extensions, using relative coinvariant rings of finite groups as prototypical models. We show that if V is a vector space and if the subgroup W of the general linear group Gl(V) is a non-modular finite reflection group and is a non-parabolic reflection subgroup, then the relative coinvariant ring cannot have a linear element of strong Lefschetz Jordan type. However, we give examples where these rings , some with non-unimodal Hilbert functions, nevertheless have (non-homogeneous) elements of strong Lefschetz Jordan type. Some of these examples are related to open combinatorial questions proposed and partially solved by G. Almkvist.