Search

Rationale: Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of quinolone residues in animal tissues, potentially accumulating in the human body and posing health risks. Investigating the correlation between mass spectrometry cleavage patterns and molecular structural features enhances the analytical framework for detecting trace or unknown impurities in quinolones. Methods: To collect data, we employed triple quadrupole linear ion trap mass spectrometry in electrospray positive ion mode. Primary mass spectrometry scanning was utilized to confirm parent ions, while secondary mass spectrometry scanning enabled the observation of fragment ions. The cleavage characteristics and pathways of the compounds were inferred from accurate mass‐to‐charge ratios obtained from both primary and secondary mass spectrometry. Results: Under soft ionization conditions, the compounds generally exhibited characteristic fragment ions of [M+H−H2O]+, [M+H−CO]+, and [M+H−H2O−CO]+. Additionally, subtle variations were observed in each compound due to differences in modifying groups. For instance, upon deacidification, the piperazine ring structure underwent breakage and rearrangement, yielding fragment ion peaks devoid of neutral molecules such as C2H5N, C3H7N, or C4H8N. Notably, compounds featuring a cyclopropyl substituent group at the N‐1 position typically exhibited characteristic fragments resulting from the loss of the cyclopropyl radical (⋅C3H5). Moreover, substituents at the N‐1 and C‐8 positions, when linked to form a six‐membered carbocyclic ring, were prone to cleavage, releasing the neutral C3H6 molecule. Conclusion: Quinolone antibiotics share structural similarities in their parent nuclei, leading to partially similar cleavage pathways. Nevertheless, distinct cleavage patterns emerge due to variations in functional groups. According to the difference of mass spectrometry cleavage patterns, it can provide an identification basis for the measured detection of antibiotics. [ABSTRACT FROM AUTHOR]

The data on the reactions of various classes of functionalized alkynyl cyclopropanes that proceed with simultaneous participation of triple bond, three-membered ring, and functional group at a cyclopropane ring are systematized. The syntheses of polysubstituted and fused furans and indoles based on electrophile-induced and catalytic transformations of alkynyl cyclopropyl carbonyl compounds and their derivatives are considered separately. The methods for isomerization of 1-alkynyl cyclopropanols and their ethers to 3-methylenecyclobutanones are described. Information on the reactions of other types of alkynyl cyclopropanes containing one or more functional groups at three-membered ring leading to different acyclic, carbo-, and heterocyclic compounds is given. Transformations of alkynyl cyclopropanes lacking the functional groups, which simultaneously involved the cyclopropane ring and the alkynyl fragment, are also discussed. [ABSTRACT FROM AUTHOR]

The activations of carbonyl compounds bearing cyclopropyl, epoxyl, azirine and aziridinyl groups by N‐heterocyclic carbene (NHC) organic catalysts are reviewed. The reactions are introduced and discussed from 3 aspects according to the activation modes involved in these transformations. A brief summary on the achievements and the remaining challenges in NHC‐catalyzed activation of cyclopropanes and their analogues is given at the end of this minireview. Our own perspectives on the future development within this highly active research field are also provided. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27—a minimal but efficient NNRTI—offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors. [ABSTRACT FROM AUTHOR]

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H' elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates. Ortho functionalisation of phenols can be achieved using N-phenoxy amide directing groups. Here a method for chemodivergent C-H alkenylation, alkylation, carboetherification, or [3 + 2] annulation is presented, with product selectivity determined by the choice of solvent. [ABSTRACT FROM AUTHOR]

Coxsackie virus B3 (CVB3) is believed to be a major cause of viral myocarditis, with virusinduced apoptosis playing an important role in pathogenesis. The purpose of this study was to characterize the antiviral activity of a novel fluoronucleoside analogue, N-cyclopropyl-4'-azido-2'-deoxy-2'-fluoro-ß-D-cytidine (NCC), against CVB3 in vitro and in vivo, and to establish whether NCC inhibits apoptosis in infected cells. In this study, HeLa cells infected with CVB3 were treated with NCC. Cell viability and apoptosis were examined. Caspase-3 and Bcl-2 levels were monitored by real-time RT PCR and Western blot analysis. For in vivo studies, BALB/c mice infected with CVB3 were treated with NCC daily. Serum markers of myocardial injury and histological studies were measured to examine myocardial injury on day 8 post-infection. To measure apoptosis, levels of Bcl-2 and caspase-3 were examined by immunohistochemistry and real-time RT-PCR. We found that NCC inhibited virus-mediated cytopathic effects in HeLa cells with an EC50 of 116.60 ± 0.32 μM. In infected mice, administration of NCC (2 mg/kg) decreased the activities of serum creatine kinase and lactic dehydrogenase, inhibited the replication of CVB3 and alleviated damage to the heart. Importantly, NCC suppressed CVB3-induced apoptosis in HeLa cells and affected the expression of apoptosis-related factors in infected mice. Together, our results demonstrate that NCC exerts significant antiviral activities against CVB3. We conclude that NCC is a potential therapeutic agent for the treatment of viral myocarditis. [ABSTRACT FROM AUTHOR]

HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PRWT) and highly-multi-PI-resistance-associated PRDRVRP51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier. [ABSTRACT FROM AUTHOR]

Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC XPZ-01 ((S)-2-amino-N-((1 R ,2 R)-1-cyano-2-(4′-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC XPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness. [ABSTRACT FROM AUTHOR]

C(sp2)‐centered homo‐ and hetero‐nuclear gold complexes have attracted widespread interests in recent decades. Studies of this type of complexes may deepen the understandings of the intermediates in Au‐catalyzed organic reactions and explore new applications in catalytic and material science. The focuses of this review include the synthesis, structural characteristics, properties and applications of C(sp2)‐centered homo‐ and hetero‐nuclear gold complexes according to different structural classifications. C(sp2)‐centered homo‐ and hetero‐nuclear gold complexes have attracted widespread interest in recent decades. In this review, recent results of the synthesis, structural characteristics, properties and applications of C(sp2)‐centered homo‐ and hetero‐nuclear gold complexes are summarized according to the classification of the structures of different complexes. [ABSTRACT FROM AUTHOR]

Abstract Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Recent studies have shown that allosteric modulation of serotonin 2C receptor (5-HT 2C) as a viable strategy for the treatment of various central nervous system (CNS) disorders. Considering the critical role of 5-HT 2C in the modulation of appetite, a selective positive allosteric modulator (PAM) of 5-HT 2C offers a new opportunity for anti-obesity therapeutic development. In this study, phenyl cyclopropyl-linked N -heterocycles were synthesized and evaluated at 5-HT 2C for agonist and PAM activity. Our study shows that imidazole linked phenyl cyclopropyl methanones has PAM activity on both 5-HT 2C and serotonin 2B receptor (5-HT 2B). Interestingly, piperazine linked phenyl cyclopropyl methanones (58) was active as PAM of 5-HT 2C (increased the E max of 5-HT to 139%), and as negative allosteric modulator (NAM) of 5-HT 2B (decreases EC 50 of 5-HT 10 times without affecting E max). Similar effect of compound 58 was observed with synthetic orthosteric agonist lorcaserin on 5-HT 2B. Molecular docking study revealed that all active compounds were binding to the predicted allosteric site on 5-HT 2C and shared a common interacting residues. Finally, compound 58 suppressed food intake in Sprague Dawley (SD) rats similar to lorcaserin after i.c.v. administration. Therefore, these results suggest that piperazine moiety is essential for dual activity (PAM & NAM) of compounds 58, and supports the hypothesis of 5-HT 2C PAM for the treatment of obesity similar to the full agonist. Graphical abstract Image 1 Highlights • A series of N -heterocycle linked phenyl cyclopropyl methanones were synthesized. • Three molecules were found active as allosteric modulators on serotonin receptors. • Compound 58 at 1 μM selectively exhibited PAM on 5-HT 2C and NAM on 5-HT 2B. • Compound 58 decreased food intake similar to full agonist lorcaserin in SD rats. [ABSTRACT FROM AUTHOR]

Rationale: The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.Objective: In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.Methods: Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.Results: ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.Conclusions: These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens. [ABSTRACT FROM AUTHOR]

Recently, a number of fentanyl analogs have been implicated in overdose deaths in Europe and in the US. So far, little is known of the molecular behavior of the structurally related subgroup; the alicyclic fentanyls. In this study, reference standards of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2,2,3,3-tetramethylcyclopropyl fentanyl (TMCPF) at a final concentration of 5 µM were incubated with cryopreserved human hepatocytes (1 × 106 cells/mL) for 0, 1, 3 and 5 h. The metabolites formed were identified by liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. The most abundant biotransformation found was N-dealkylation (formation of normetabolites) and oxidation of the alicyclic rings. As ring size increased, the significance of N-dealkylation decreased in favor of alicyclic ring oxidation. An example of this was cyclopropyl fentanyl, with a three-carbon ring, whose normetabolite covered 82% of the total metabolic peak area and no oxidation of the alicyclic ring was observed. In contrast, TMCPF, with a seven-carbon ring structure, rendered as much as 85% of its metabolites oxidized on the alicyclic ring. Other biotransformations found included oxidation of the piperidine ethyl moiety and/or the phenethyl substructure, glucuronidation as well as amide hydrolysis to form metabolites identical to despropionyl fentanyl. Taken together, this study provides a base for understanding the metabolism of a number of structurally related fentanyl analogs formed upon intake. [ABSTRACT FROM AUTHOR]

1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus non-structural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability. 2. In vitro metabolism studies of two compounds from this C6-substituted series revealed an NADPH-dependent bioactivation pathway leading to the formation of multiple glutathione (GSH) conjugates. Analysis of these conjugates by LC-MS and NMR demonstrated that the cyclopropyl group was the site of bioactivation. Based on the putative structures and molecular weights of the cyclopropyl-GSH conjugates, a multi-step mechanism was proposed to explain the formation of these metabolites by P450. This mechanism involves hydrogen atom abstraction to form a cyclopropyl radical, followed by a ring opening rearrangement and reaction with GSH. 3. These findings provided important information to the medicinal chemistry team which responded by replacing the cyclopropyl ring with a gem-dimethyl group. Subsequent compounds bearing this feature were shown to avert the bioactivation pathways in question. [ABSTRACT FROM AUTHOR]

We demonstrate the versatile use of the cyclopropylmethyl group to protect phenols through the total synthesis of two benzofuran‐based natural products, that is, anigopreissin A and the resveratrol–piceatannol hybrid. This protecting group is a good alternative to the conventional methyl group, owing to the feasibility of introduction, stability under a variety of conditions, and its relative ease of removal under different acidic conditions. Don′t be overprotective: The cyclopropylmethyl protecting group is successfully used as an alternative to methyl ethers in the total synthesis of anigopreissin A and resveratrol–piceatannol hybrid. [ABSTRACT FROM AUTHOR]

In order to track the source of duplicated peaks in the 1H-NMR spectrum of Ticagrelor, variable-temperature NMR (VT-NMR) experiment was carried out with temperature increasing from 300 to 343 K. The result showed that the phenomenon was brought forth by coexistence of conformational isomers. Subsequently, conformational search was carried out by molecular mechanics (MM) stimulations associating with quantum mechanics (QM) calculations. The results revealed that the isomers resulting in duplicated proton peaks were introduced by the rotation of 2,4-diflurophenyl group on C3’position of cyclopropyl. Finally, noncovalent interaction (NCI) topological analysis of the conformers exhibited that CH-π interactions and H-bonds play important roles in controlling the population of conformers of ticagrelor. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Direct access to diastereoselective spirooxindoles framework. • Control over [3 + 2] and [2 + 1] annulation by switching catalysts. • Construction of vicinal quaternary spiro centers with three contiguous stereocenters. • Broader substrate scope. • Total of 32 examples with very good yields and high diastereoselectivity. Abstract A highly diastereoselective organocatalytic synthesis of cyclopentenyl bis-spirooxindoles and cyclopropyl spirooxindoles has been achieved via [3 + 2] and [2 + 1] annulations. The tertiary amine catalysts have been effectively employed to tune the cycloaddition of isatin-derived MBH carbonates and 3-methyleneoxindoles for the outcome of two different spirooxindole frameworks with vicinal quaternary spiro centers and three contiguous stereocenters. The reactions worked under mild and practical conditions to afford the spirooxindoles in good to excellent yields with very high diastereoselectvity. [ABSTRACT FROM AUTHOR]

New spirocyclopropyl derivatives of lupane series were synthesised and their spatial structure was determined by X-ray analysis. These compounds may be used as chiral dopants for cholesteric liquid-crystal compositions which are applied in the surface stabilized cholesteric texture and polymer stabilized cholesteric texture displays with low power consumption. The relationship between stereostructure of the synthesised substances and their ability to induce cholesteric mesophase in different nematic solvents were examined. The highest values of the helical twisting power | β | (213,8 ± 1,1) and (230,5 ± 4,3) mkm -1 mol ⋅ pats -1 in the 4′-pentyl-1,1′-biphenyl-4-carbоnitrile as a nematic solvent were showed by the (1 S ,2 S )-1-(1-phenyl-3-(4-tolyl)-1 H -pyrazole-4-yl)-2,2′-spirocyclopropylallobetulone and (1 S ,2 S )-1-(3-(4-methoxyphenyl)-1-phenyl-1 H -pyrazole-4-yl)-2,2′-spirocyclopropylallobetulone correspondingly. [ABSTRACT FROM AUTHOR]

Interactions and natural bond orbital analysis of cyclopropylpiperazine(cppp) and B- or Al-doped C60 fullerenes are investigated by quantum mechanical calculations. The structural and electronic properties, such as NH stretching vibrations, nuclear magnetic shielding tensors of 27Al and 11B nuclei or the energy gap are also investigated. All calculations are carried out in the gas phase and water media. Results of the bond order and the binding energy suggest that chemisorption occurs between the cppp nitrogen atom and boron or aluminum atoms of fullerenes. The Alcomplex in water is foundto have the highest binding energy. Further, AlC59...cppp complexes have a slightly higher kinetic stability and a low chemical reactivity. However, BC59...cppp works as a function-type sensor for cppp. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of cyclopropyl silyl ketones possessing a hydrocarbon group at 1-position of three-membered ring. • Reaction of sulfoxonium ylide with α,β-unsaturated acylsilanes. • The Corey-Chaykovsky cyclopropanation and subsequent silylation of α,β-unsaturated aldehydes. Abstract The synthesis of cyclopropyl silyl ketones possessing a hydrocarbon group at 1-position of three-membered ring was investigated. The reaction of sulfoxonium ylide with α,β-unsaturated acylsilanes derived from α,β-unsaturated aldehydes did not afford the desired acylsilane derivatives. Instead, the corresponding silyl enol ethers were yielded exclusively. On the other hand, the Corey-Chaykovsky cyclopropanation of α-substituted α,β-unsaturated aldehydes proceeded well to give 1-substituted cyclopropyl aldehydes. The silyl substitution of formyl proton in the obtained aldehydes via umpolung of carbonyl group afforded the target acylsilanes. [ABSTRACT FROM AUTHOR]

The reaction of oxime‐tethered 1,6‐enynes with a cationic gold(I) catalyst demonstrates a great potential for the synthesis of a range of heterocycles in a diastereospecific fashion. The control of the configuration of the oxime and the alkene of the enyne moiety is the key to selectively obtain dihydro‐1,2‐oxazines, isoxazolines or dihydropyrrole‐N‐oxides as single diastereoisomers. As supported by DFT calculations, these cascade reactions proceed stepwise, by the intramolecular addition of the O or N atom of the oxime onto cyclopropyl gold(I) carbene intermediates. In this study, a rare [3,3]‐sigmatropic rearrangement of nitrones is also observed. Selective cascade: A new gold(I)‐catalyzed cyclization cascade of oxime‐tethered enynes has been developed that allows for the selective preparation of dihydro‐1,2‐oxazines, dihydroisoxazoles and dihydropyrrole N‐oxides generally as single diastereomers. In addition, these last compounds may undergo a sigmatropic rearrangement to give rise to migrated dihydropyrrole N‐oxides. [ABSTRACT FROM AUTHOR]

A series of 14β-acyl substituted 17-cyclopropylmethyl-7,8-dihydronoroxymorphinone compounds has been synthesized and evaluated for affinity and efficacy for mu (MOP), kappa (KOP), and delta (DOP) opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors. The majority of the new ligands displayed high binding affinities for the three opioid receptors, and moderate affinity for NOP receptors. The affinities for NOP receptors are of particular interest as most classical opioid ligands do not bind to NOP receptors. The predominant activity in the [35S]GTPγS assay was partial agonism at each receptor. The results are consistent with our prediction that an appropriate 14β side chain would access a binding site within the NOP receptor and result in substantially higher affinity than displayed by the parent compound naltrexone. Molecular modeling studies, utilizing the recently reported structure of the NOP receptor, are also consistent with this interpretation. [ABSTRACT FROM AUTHOR]

New schemes of synthesis of (2S)-4-methyl- and (2S)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-carbaldehydes have been developed with the goal of obtaining C22-C27 fragments of fijianolides and their synthetic analogs on the basis of transformations of cyclopropanol intermediates. The C22-C27 block of fijianolides A and B has been synthesized. [ABSTRACT FROM AUTHOR]

Pyrazole derivatives bearing a cyclopropyl group at C3-position and an amino substituent at C5 were successfully employed in palladium-catalyzed direct arylations. These couplings were performed using air-stable PdCl(C 3 H 5 )(dppb) catalyst associated to KOAc as inexpensive base, and afforded regioselectively the C4-arylated pyrazoles without decomposition of the cyclopropyl unit and formation of amination products. A wide variety of functional groups on the aryl bromide including electron-withdrawing and electron-donating ones such as nitrile, nitro, propionyl, ester, trifluoromethyl, chloro, fluoro or methoxy was tolerated. Moreover, from 5-aminopyrazoles bearing N -2′-bromoaryl or 2′-bromobenzenesulfonamide substituent on the amino group, intramolecular Pd-catalyzed direct arylations allowed the formation of tricyclic compounds by formation of 5- or 6-membered rings. © 2018 Elsevier Science. All rights reserved. [ABSTRACT FROM AUTHOR]

Abstract: The asymmetric ring‐opening reaction of cyclopropyl ketones with indoles has been realized by using a N,N′‐dioxide/scandium(ΙΙΙ) complex as catalyst. The corresponding 3‐alkylated indole derivatives were obtained in moderate to excellent yields with good ee values. Moreover, a possible transition state was proposed on the basis of experimental studies and X‐ray structure of product. [ABSTRACT FROM AUTHOR]

Novel chiral gold(III) complexes, based on bisoxazoline (BOX) and 2‐pyridyl‐(–)menthol ligands, were prepared and characterised (X‐ray), and their catalytic properties in cyclopropanation reactions of propargyl esters with alkenes were explored. The BOX‐AuIII catalysts gave excellent results for fast cyclopropanation and subsequent in situ cis‐to‐trans vinylcyclopropyl isomerization. AuI and AuIII catalytic species showed different abilities to tune the reactions and transform the initially formed cis product into the isomerized trans product. The appropriate choice of gold(I) or gold(III) complex enabled highly stereoselective formation of cis or trans products (up to 99 % dr), in high yields (63–98 %). The pure cis isomers were used in isomerization studies, showing that rapid cis‐to‐trans isomerization took place at room temperature in the presence of BOX‐AuIII catalysts. [ABSTRACT FROM AUTHOR]

In the present paper we describe the optimization and the application of a chromatographic method suitable to get all four diastereoisomers of C24–C25 cyclopropyl dafachronic acid derivatives in sufficient amount for their biological appraisal towards the nuclear hormone receptor transcription factor DAF-12. A preliminary column screening of six anion exchange type Cinchona alkaloid-based chiral stationary phases (CSPs) allowed to identify the one with a quinine scaffold and carrying a O -9-(3,5-bis(trifluoromethyl)phenyl) moiety at C9 position as the best CSP. Few modifications of the experimental conditions revealed that a content of 18 mM acetic acid used as counterion and displacer in acetonitrile and a column temperature fixed at 35 °C were optimal for the simultaneous discrimination of all four diastereoisomers with a 1.0 mL/min flow rate. With such conditions, transoid ( S , S ) and ( R , R ) diastereoisomers were resolved with R S > 1.4. With non chiral reversed-phase columns, neither the cisoid nor the transoid diastereoisomers could be resolved. This way, ca. 1.0 mg of each stereoisomer was isolated with a diastereomeric purity >98%, suitable for the following biological tests. The indirect stereochemical assignments of the four diastereoisomers, and hence the corresponding chromatographic elution order (24 R ,25 R ) < (24 S ,25 S ) < (24 R ,25 S ) < (24 S ,25 R ) were made in an analogy manner on the basis of the resolution of fully assigned and structurally very similar ursodeoxycholic acid derivatives. As support of this indirect way of assigning the absolute configuration of the C24 and C25 chiral centre a molecular modeling procedure based on dynamic simulation was successfully applied. [ABSTRACT FROM AUTHOR]

Abstract: Racemic cyclopropyl ketones undergo enantioselective rearrangement to deliver the corresponding dihydrofurans in the presence of a chiral phosphoric acid as the catalyst. The reaction involves activation of the donor‐acceptor cyclopropane substrate by the chiral Brønsted acid catalyst to promote the ring‐opening event, thus generating a carbocationic intermediate that subsequently undergoes cyclization. Computational studies and control experiments support this mechanistic pathway. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs. Methods: Several novel cyclopropyl derivatives were designed and synthesized. The binding affinities of these compounds as well as the selectivity on subtype of estrogen receptor (ER) were assessed by fluorescence polarization. The antagonistic activity was also evaluated by dual‐luciferase reporter assay. Key findings: Our data identified five compounds (9a, 9b, 9d, 9e and 9f) with a higher selectivity on ERα than ERβ subtype, warranting further development as a subtype‐selective ER modulator. The study of antiestrogen activity also demonstrated that compounds 9a, 9c‐f acted as full functional antagonists for ERα. These compounds had no or very low cytotoxicity. Conclusions: Although these cyclopropyl derivatives showed lower binding affinities on ERs compared to 17β‐estradiol, five of these compounds exhibited binding to ERα only and therefore might serve as a promising lead compound for further development of novel subtype‐selective SERMs. [ABSTRACT FROM AUTHOR]

Since 6‐isopropyl‐ (11) and 6‐isobutyl‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one (12) instead of the expected marine odor had been reported to possess lily‐of‐the‐valley notes, albeit weaker than benchmark odorants, the influence of a cyclopropyl ring instead of a methyl branching on the olfactory properties was investigated. 6‐Cyclopropyl‐ (27), 6‐(2′‐methylcyclopropyl)‐ (32) and 6‐(cyclopropylmethyl)‐2H‐benzo[b][1,4]dioxepin‐3(4H)‐one (39) were thus synthesized from 2,3‐dimethoxybenzaldehyde (22) by a synthetic sequence consisting of Wittig methylenation/ethylenation/homologation with (methoxymethyl)triphenylphosphonium chloride, followed by cyclopropanation, demethylation, Williamson etherification with 3‐chloro‐2‐(chloromethyl)prop‐1‐ene, and Katsuki–Sharpless oxidation. The odor thresholds of the target structures 27, 32, and 39, which are all floral‐green lily‐of‐the‐valley odorants, lie in the range of that of Lilial (1), with the 6‐cyclopropyl derivative 27 being the most potent (th 0.065 ng/l air). Particularly impressive was the close resemblance of the 6‐(cyclopropylmethyl) derivative 39 with Bourgeonal (3), which was rationalized by a superposition analysis. [ABSTRACT FROM AUTHOR]

The molecular structure and conformational behavior of 3-cyclopropyl-1,2-dimethyldiaziridine have been for the first time experimentally studied by gas-phase electron diffraction and quantum chemical calculations. The two most stable conformers at 298 K possess anti and gauche mutual ring orientation (with prevalence of the anti conformer) whereas only one anti conformer is observed in solution. The determined structural parameters of gaseous 3-cyclopropyl-1,2-dimethyldiaziridine have been compared with those for 3,3-bidiaziridine structural analogues in the crystal phase. The simple and convenient procedure for the synthesis of 3-cyclopropyl-1,2-dimethyldiaziridine comprising cyclopropane and diaziridine rings in one molecule was developed. The standard enthalpy of formation of 3-cyclopropyl-1,2-dimethyldiaziridine in the gas phase was calculated using Gaussian-4 theory, yielding value of 281.9 ± 5.0 kJ/mol. [ABSTRACT FROM AUTHOR]

Background: Cyclopropyl-methoxycarbonyl metomidate, or ABP-700, is a second generation analogue of etomidate, developed to retain etomidate's beneficial haemodynamic and respiratory profile but diminishing its suppression of the adrenocortical axis. The objective of this study was to characterise the safety and efficacy of 30-min continuous infusions of ABP-700, and to assess its effect on haemodynamics and the adrenocortical response in healthy human volunteers.Methods: Five cohorts involving 40 subjects received increasing infusion doses of ABP-700, propofol 60 μg kg-1 min-1 or placebo. Safety was evaluated through adverse event (AE) monitoring, safety laboratory tests, and arterial blood gasses. Haemodynamic and respiratory stability were assessed by continuous monitoring. Adrenocortical function was analysed by adrenocorticotropic hormone (ACTH) stimulation tests. Clinical effect was measured using the modified observer's assessment of alertness/sedation (MOAA/S) and continuous bispectral index monitoring.Results: No serious AEs were reported. Haemodynamic and respiratory effects included mild dose-dependent tachycardia, slightly elevated blood pressure, and no centrally mediated apnoea. Upon stimulation with ACTH, no adrenocortical depression was observed in any subject. Involuntary muscle movements (IMM) were reported, which were more extensive with higher dosing regimens. Higher dosages of ABP-700 were associated with deeper sedation and increased likelihood of sedation. Time to onset of clinical effect was variable throughout the cohorts and recovery was swift.Conclusions: Infusions of ABP-700 showed a dose-dependent hypnotic effect, and did not cause severe hypotension, severe respiratory depression, or adrenocortical suppression. The presentation and nature of IMM is a matter of concern.Clinical Trial Registration: NTR4735. [ABSTRACT FROM AUTHOR]

Abstract: The aggregate formation of trans‐2,3‐dimethylcyclopropyllithium (2) was studied in diethylether (DEE). With the help of the isotopic fingerprint method three clusters, a monomer, a dimer, and a fluxional tetramer in the ratio 1.00:0.53:0.22 were identified at 187 K. In the presence of 1 equivalent of LiBr cyclopropyllithium (1) forms in DEE at 163 K a mixed dimer and a mixed tetramer, while in THF a mixed dimer dominates. Under the same conditions 2 and 2,2,3,3‐tetramethylcyclopropyllithium (3) form in the solvent mixture DEE/THF (1:1) mixed dimers, as does 2 also in THF. [ABSTRACT FROM AUTHOR]

D–A cyclopropanes bearing a simple cyclopropyl group as donor are shown to undergo a variety of [3+n]-cycloaddition reactions (n = 2–4). This behavior contrasts sharply with that of common D–A cyclopropanes with aliphatic donors. Kinetic experiments demonstrate that, in terms of donor ability, the cyclopropyl substituent lies between electron-rich and electron-neutral aryl donors. [ABSTRACT FROM AUTHOR]

The reduction of 2-cyclopropylcarbonyl-, 2-(thiophen-2-yl)carbonyl-, and 2-arylcarbonylbenzonitriles with sodium tetrahydridoborate afforded 3-cyclopropyl-, 3-(2-thiophen-2-yl)-, and 3-arylphthalides, respectively, in high yields. Under analogous conditions, 3-cyanobenzophenones were converted to the corresponding 3-cyanobenzhydrols. [ABSTRACT FROM AUTHOR]

Abstract: Reminiscent of biological systems, the increasingly popular concept of remote activation allows a greater strategic synthetic flexibility for the development of novel synthetic organic methodologies. In this Communication, we report that commercially available ruthenium (II)‐based “alkene zipper catalyst” enables the selective transformation of a large variety of ω‐alkenyl cyclopropylcarbinols into stereodefined unconjugated (E)‐acyclic aldehydes bearing a quaternary stereocenter through an isomerization followed by a retro‐ene reaction. To unravel this peculiar catalytic property of the “alkene zipper” and shed some light on the mechanism, a series of control experiments were performed. [ABSTRACT FROM AUTHOR]

Synthetic analogues of plant hormone abscisic acid (ABA) bearing a yet unexplored head group motif were prepared based on a combination of agrochemical experience, in vivo hits and structure-based design. It could thus be explored how modifying key parts of ABA's cyclohexenone unit influenced receptor affinity and in vivo efficacy against drought stress in selected crops. Cyano-cyclopropyl groups proved to be suitable replacements of the cyclohexanone moiety leading to ABA analogues with strong activity in vitro and in vivo. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings as the key steps. Combining novel cyano-cyclopropyl headgroups with previously identified substituents in the terpenoid side chain afforded the most promising effects against drought stress in crops, particularly canola and wheat. [ABSTRACT FROM AUTHOR]

Exposure to the toxins methylene cyclopropyl acetic acid (MCPA) and methylene cyclopropyl glycine (MCPG) of unripe ackee and litchi fruit can lead to hypoglycemia and death; however, the molecular mechanisms by which MCPA and MCPG cause hypoglycemia have not been established in vivo. To determine the in vivo mechanisms of action of these toxins, we infused them into conscious rodents and assessed rates of hepatic gluconeogenesis and ketogenesis, hepatic acyl-CoA and hepatic acetyl-CoA content, and hepatocellular energy charge. MCPG suppressed rates of hepatic ß-oxidation as reflected by reductions in hepatic ketogenesis, reducing both short- and medium-chain hepatic acyl-CoA concentrations. Hepatic acetyl-CoA content decreased, and hepatic glucose production was inhibited. MCPA also suppressed ß-oxidation of short-chain acyl-CoAs, rapidly inhibiting hepatic ketogenesis and hepatic glucose production, depleting hepatic acetyl-CoA content and ATP content, while increasing other short-chain acyl- CoAs. Utilizing a recently developed positional isotopomer NMR tracer analysis method, we demonstrated that MCPA-induced reductions in hepatic acetyl-CoA content were associated with a marked reduction of hepatic pyruvate carboxylase (PC) flux. Taken together, these data reveal the in vivo mechanisms of action of MCPA and MCPG: the hypoglycemia associated with ingestion of these toxins can be ascribed mostly to MCPA- or MCPG-induced reductions in hepatic PC flux due to inhibition of ß-oxidation of short-chain acyl-CoAs by MCPA or inhibition of both short- and medium-chain acyl- CoAs by MCPG with resultant reductions in hepatic acetyl-CoA content, with an additional contribution to hypoglycemia through reduced hepatic ATP stores by MCPA. [ABSTRACT FROM AUTHOR]

We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity. [ABSTRACT FROM AUTHOR]

A thorough study on radical-induced cyclopropyl ring fragmentation with encompassed olefinic and cyclopropane environment has been performed. Interestingly, the fragmentation has occasioned onto a stereoselective synthesis of 3-allyltrans-2,3-dihydrobenzofurans with impressive yields. Thetrans-dihydrobenzofurans are present as central core in many molecules of medicinal interest and the present protocol deliver a straight forward access to the embedded molecular architecture. [ABSTRACT FROM AUTHOR]

A series of polycyclic hydrocarbons containing cyclopropane moieties 1,2-annelated or spiro-condensed with a cyclooctane ring were investigated under oxidative conditions. Four oxidizing systems (O3 on SiO2, a dioxirane derived from trifluoroacetone, CrO3, and RuO4, generated in situ), were tested to evaluate and compare their reactivity and usefulness. RuO4 was found to be the best of them, considering its oxidative power together with the simple operating procedure. Conditions for the specific oxidation of polycyclic hydrocarbons were found. New cyclooctane derivatives containing cyclopropyl carbonyl moieties were obtained. [ABSTRACT FROM AUTHOR]

Abstract: Described is an unprecedented NHC‐catalyzed (NHC=N‐heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three‐step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio‐ and stereodivergent synthesis of either 1,2‐amino alcohols/diamines or 1,4‐fluoro alcohols with excellent diastereo‐ and enantiopurity. [ABSTRACT FROM AUTHOR]

Chiral cyclopropyl- and cyclobutylboronic esters and -silanes have become attractive intermediates for the preparation of functionalized small rings. This review highlights the stereoselective methods developed for their preparation, including both diastereo- and enantioselective approaches. 1 Introduction 2 Stereoselective Synthesis of Cyclopropyl- and Cyclobutylboronates and -silanes 2.1 Diastereoselective Synthesis of Cyclopropyl- and Cyclobutylboronates and -silanes 2.2 Asymmetric Synthesis of Cyclopropyl- and Cyclobutylboronates and -silanes 3 Conclusions. [ABSTRACT FROM AUTHOR]

A method for intermolecular [3+2] cycloaddition between aryl cyclopropyl ketones and alkenes involving the combination of Lewis acid and photoredox catalysis is reported. In contrast to other more common methods for [3+2] cycloaddition, these conditions operate using a broad range of both electron-rich and electron-deficient reaction partners. The critical factors predicting the success of these reactions is the redox potential of the cyclopropyl ketone and the ability of the alkene to stabilize a key radical intermediate. [ABSTRACT FROM AUTHOR]

We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11mper dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range. [ABSTRACT FROM AUTHOR]

The possible mechanisms of 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed ring expansion of cyclopropyl ketone for forming dihydrofurans have been studied using density functional theory (DFT). According to the calculated results, the reaction occurs via two competing paths including paths A and B, which lead to two different products ( i.e. 2-methyl-4,5-dihydrofuran and 2-phenyl-4,5-dihydrofuran), respectively. Path A is revealed to be more energetically favorable than path B, which is consistent with the experimental observation. Two reaction steps are contained in the favorable path: (1) nucleophilic addition of DABCO to cyclopropyl ketone coupled with three-membered ring opening; (2) five-membered ring closure process accompanied with dissociation of DABCO and product via the S N 2-type transition state. Moreover, global reactivity index (GRI) and non-covalent interaction (NCI) analyses were performed to disclose the role of catalyst and explain the chemoselectivity. By analysing of the efficiency of different catalysts ( i.e. tricyclohexylphosphine (PCy 3 ), triphenylphosphine (PPh 3 ), tributylphosphine (PBu 3 ), 4-dimethylaminopyridine (DMAP), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)), it was found that the stronger nucleophilicity of amine catalyst would be corresponding to the lower energy barrier of the ring expansion reaction. [ABSTRACT FROM AUTHOR]

A Ni−Al bimetallic catalyzed enantioselective cycloaddition reaction of cyclopropyl carboxamides with alkynes has been developed. A series of cyclopentenyl carboxamides were obtained in up to 99% yield and 94% ee. The bifunctional-ligand-enabled bimetallic catalysis proved to be an efficient strategy for the C−C bond cleavage of unreactive cyclopropanes. [ABSTRACT FROM AUTHOR]

The density and viscosity of the cyclopropyl methyl ketone (CPMK) + 2-acetylbutyrolactone (ABL) and CPMK + 5-chloro-2-pentanone (CPE) binary mixtures were measured at the temperature range of 303.15 to 333.15 K at atmospheric pressure (about 101.325 ± 0.3 kPa). The excess molar volume and viscosity deviation were calculated based on the experimental data of density and viscosity, and they could be accurately described by the Redlich-Kister equation. In addition, the vapor-liquid equilibrium (VLE) data for the CPMK-ABL binary system were measured at atmospheric pressure. It was shown that there is no azeotrope in this binary mixture. The VLE data were correlated with NRTL, Wilson, and UNIQUAC models and the interaction parameters obtained were reported. The prediction accuracies of these models were about the same. [ABSTRACT FROM AUTHOR]