14-membered Ring Research Articles

Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives.

The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. The structure-activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116.

The clean synthesis and confirmatory structural characterization of new 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-cyano based on Kojic acid

A valuable and clean method was developed for the synthesis of the group of different novel 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles containing a 2-aminopyran moiety by using of azido kojic acid and various 2-arylidinemalononitriles in the presence of NH4Cl as a catalyst in a green solvent (ethanol) with excellent yields. All structures were analyzed by FT-IR, 1H, 13C NMR spectroscopy, and representatively, one compound was analyzed by X-ray crystallography technique. Crystallographic analyses indicated that of this compound a dimer formed via two weak intermolecular hydrogen bonds with d(N···O) distances of 2.927 A and made a 14-membered ring with centrosymmetric (Ci) form.

Non-centrosymmetric BaNaP3O9 with a short deep-ultraviolet cutoff edge

A new nonlinear optical (NLO) material, namely, BaNaP3O9 was synthesized by high temperature solution method using PbO as the flux. Crystal of BaNaP3O9 with the non-centrosymmetric P212121 space group displays a novel topological three dimensional (3D) structure with tremendous [Ba4Na4O40] 16-membered ring (16-MR) composed by the BaO8, NaO6 polyhedra, which alternately connected each other by sharing two oxygen atoms. The phosphate compound has a short deep-ultraviolet (deep-UV) cut-off edge about 177 nm and shows a second harmonic generation (SHG) response (0.3 × KDP). Some related optical properties and electronic structures derived from first-principles calculations, were explored.

Hydrothermal Synthesis, Study, and Classification of Microporous Uranium Silicates and Germanates.

Four novel uranyl silicates and germanates with framework structures, K4Na2(UO2)3(Si2O7)2·3H2O, K4Na2(UO2)3(Ge2O7)2·3H2O, H3O(UO2)2(HGe2O7)·2H2O, and Na2(UO2)GeO4, have been synthesized by means of the hydrothermal method. The structures of the title compounds were refined by single-crystal X-ray diffraction and characterized by Raman spectroscopy. We used the method of secondary building units (SBUs) for a crystal chemical analysis of the 3D framework and their topologies. The framework of the K4Na2(UO2)3(T2O7)2·3H2O (T = Si, Ge) series exhibits large 14-membered rings and smaller 8-membered rings which are built upon [UT4] pentamers. The internal size of the largest pores is approximately 12.39 × 3.33 Å2. H3O(UO2)2(HGe2O7)·2H2O is based on 10-membered rings with intermediate sized pores. They are built upon [U2Ge2] tetramers with 7-fold-coordinated U. The internal dimension of the pores in H3O(UO2)2(HGe2O7)·2H2O is smaller compared to the K4Na2(UO2)3(T2O7)2·3H2O (T = Si, Ge) series with ∼5.91 × 5.33 Å2. Its topology is similar to several uranium germanate synthetic phases and silicate minerals, especially α- and β-uranophane which are constructed from similar building units. A novel 3D framework type of Na2(UO2)GeO4 with 8-membered rings demonstrates the smallest free volume in the family of porous uranium germanates. It crystallizes in tetragonal symmetry and is built upon corner sharing of [UGe4] pentamers. The size of the channels is ∼6.76 × 4.27 Å2. The vibrational bands in Raman spectra were associated with pyro-(Si2O7)6- and -(Ge2O7)6- groups, with the Ge-OH bond and with H3O+ cations, confirming the results of the X-ray crystallographic structural characterization. We systemized existing uranyl silicates and germanates based on their building units and chemical composition. We found a simple structural dependence between synthetic conditions and chemical composition.

Comparative Analysis of Bacterial Cytochromes P450 Involved in the Biosynthesis of 16‐ Membered Ring Macrolide Antibiotics

Members of the cytochrome P450 superfamily of monooxygenases (P450s) are some of nature's most ubiquitous and versatile enzymes for performing oxidative metabolic transformations. Their unmatched ability to selectively functionalize C–H bonds has led to their growing employment in academic and industrial settings for the production of fine and commodity chemicals. Many of the most interesting and potentially biocatalytically useful P450s come from microorganisms, where they catalyze key tailoring reactions in natural product biosynthetic pathways. While most of these enzymes act on structurally complex pathway intermediates with high selectivity, they often exhibit narrow substrate scope, thus limiting their broader application. In the present work, we biochemically and structurally characterized diverse bacterial P450s involved in the biosynthesis of 16-membered ring macrolide antibiotics with significant potential for development into robust biocatalysts for the late-stage functionalization of complex molecules. Following exploratory efforts to probe the reactivity properties of the P450 MycCI from the mycinamicin biosynthetic pathway, we discovered that the enzyme exhibits appreciable activity on several 16-membered ring macrolactones independent of their glycosylation state. These results were corroborated by performing equilibrium substrate binding and kinetics experiments along with X-ray crystallographic analysis of MycCI bound to its native substrate. We also characterized TylHI, a homologous P450 from the tylosin pathway, and showed that its substrate scope is severely restricted compared with that of MycCI. Turnover and equilibrium binding experiments with substrate analogs revealed that TylHI exhibits a strict preference for 16-membered ring macrolides bearing the deoxyamino sugar mycaminose. These results were partially explained through analysis of the X-ray crystal structure of TylHI in complex with its native substrate together with biochemical characterization of several sitedirected mutants. Comparative analysis of the MycCI/TylHI homolog ChmHI from the chalcomycin biosynthetic pathway provided a basis for constructing MycCI/TylHI chimeras in order to gain further insight into the features dictating the differences in the reactivity profiles of these two related P450s. These experiments unveiled the central role of the BC loop region in influencing the binding of 16-membered ring substrates to MycCI and TylHI. Overall, our studies have shed light on the molecular-level details underpinning the unique catalytic divergence of two homologous biosynthetic P450s and point toward specific regions in each protein that may be targeted in future efforts to rationally engineer novel P450-based biocatalysts. Support or Funding Information NSF under the CCI Center for Selective C–H Functionalization (CHE-1205646 and CHE-1700982), NIH (R01-GM078553, R35-GM118101, and T32-GM008353), University of Michigan Rackham Predoctoral Fellowship Physiological reactions catalyzed by P450s MycCI and TylHI in their respective biosynthetic pathways. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Quorumolides A-C, Three Cembranoids from Euphorbia antiquorum.

Three highly modified cembranoids, quorumolides A-C (1-3), were isolated from Euphorbia antiquorum. Compound 1 is the first example of a cembranoid embedding an α,β-unsaturated-γ-lactone and a tetrahydro-2H-pyran motif within the 14-membered ring. Biosynthetically, it is particularly noteworthy that the stereochemistries of C-2 and C-12 in the pyran ring of 1-3 were opposite to those of marine-derived rare cembranoids.

New bioactive cyclopeptide alkaloids with rare terminal unit from the root bark of Ziziphus cambodiana.

Six new 14-membered ring cyclopeptide alkaloids, cambodines A–F (1–6), and two known compounds, frangufoline (7) and lotusanine B (8), were isolated from the root bark extract of Ziziphus cambodiana Pierre. Their structures and configurations were established based on 1D and 2D NMR, HRMS, ECD, and X-ray crystallographic data. Compounds 1 and 3 are rare 5(14)-type cyclopeptide alkaloids that possess an imidazolidin-4-one ring in the terminal unit. The cyclopeptides were tested for their in vitro antiplasmodial, antitubercular, and cytotoxic effects against three cancer cell lines. Compound 3 showed significant antiplasmodial activity against the malarial parasite Plasmodium falciparum, with an IC50 value of 6.09 μM.

In Situ Methylene Capping: A General Strategy for Efficient Stereoretentive Catalytic Olefin Metathesis. The Concept, Methodological Implications, and Applications to Synthesis of Biologically Active Compounds.

In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.

Solvothermal synthesis, crystal structures and characterization of open-framework metal (CoII and MnII) phosphites with helical channels and 16-membered rings

Two new 3D open-framework metal phosphites [(CH3)2NH2]2Co3(HPO3)4 (1) and [(CH3)2NH2]2Mn3(HPO3)4 (2) have been solvothermally synthesized. Single-crystal X-ray diffraction analysis shows that complexes 1 and 2 are isomorphic structures, with left/right-handed helical channels and 16-membered ring channels. Complex 2 represents the first monometallic four-coordinate manganese phosphite. These two phosphite complexes 1 and 2 display antiferromagnetic behavior.

A Cyclopeptide and a Tetrahydroisoquinoline Alkaloid from Ophiorrhiza nutans.

A new cyclopeptide, ophiorrhisine A (1), a new tetrahydroisoquinoline alkaloid, 7',10-dide-O-methylcephaeline (2), two known β-carboline alkaloids, and four known tetrahydroisoquinoline alkaloids were isolated from Ophiorrhiza nutans (Rubiaceae). Compound 1 is a tetrapeptide possessing a 14-membered paracyclophane ring and a novel N,N,N-trimethyltyrosine residue in the side chain. The stereochemistry at the aryl-alkyl ether bond was different from that of other known 14-membered paracyclophanes. The structure of 2 was established by spectroscopic analysis and semisynthesis.

Identification of impurities in macrolides by liquid chromatography–mass spectrometric detection and prediction of retention times of impurities by constructing quantitative structure–retention relationship (QSRR)

Macrolides are multicomponent drugs whose impurity control is always a challenge demanding analysis method with good sensitivity and selectivity. Three separate, sensitive, accurate liquid chromatography tandem mass spectrometry methods (LC–MS) were developed for the measurement of three 16-membered ring macrolides (josamycin, josamycin propionate and midecamycin acetate) and related substances in commercial samples. The characteristics of impurities in macrolides were summarized as useful guidance for the impurity analysis of this class of drugs. For each drug, a large number of unknown components have been detected with the high-sensitive MS detector and possible structures of the majority of them were postulated based on the summarized fragmentation rules of 16-membered ring macrolides. A QSRR model was constructed by multilinear regression to predict the retention times of identified impurities which were not detected by the LC–MS methods, without obtaining their reference standards. Satisfactory performance was obtained during leave-one-out cross-validation with a predictive ability (Q2) of 0.95. The generalisation ability of the model was further confirmed by an average error of 2.3% in external prediction. The best QSRR model, based on eight molecular descriptors, exhibited a promising predictive performance and robustness.

Structure and hydrogen bonds of cyclohexapeptide RA-VII by molecular dynamics simulations and quantum chemical calculations

We computationally examined the structure of anti-tumour bicyclic hexapeptide RA-VII. This peptide adopts three conformations (confs.), A, B and C, in dimethyl sulfoxide (DMSO). Although it was experimentally reported that the structure of conf. A is important for anti-tumour activity, the dynamics of confs. A, B and C are not well known. We performed quantum chemical calculations and molecular dynamics (MD) simulations of RA-VII in DMSO. The MD simulations indicated two different local stable structures for conf. C: a structure containing a bent 18-membered ring and another structure containing a rotated peptide bond between Tyr6 and d-Ala1. The root-mean-square fluctuation of the 14-membered ring for conf. A was larger than that for confs. B and C. Ala4 formed intramolecular hydrogen bonds more often in conf. A than in the other conformations. A large number of hydrogen bonds and large structural fluctuations are important for the anti-tumour activity of RA-VII. Our results for the structural change of conf. C and the analysis of the dynamics for confs. A, B and C may contribute to the design of new analogues of cyclic peptides.

Synthesis, Crystal Structures and Properties of Ferrocenyl Bis-Amide Derivatives Yielded via the Ugi Four-Component Reaction.

Ten ferrocenyl bis-amide derivatives were successfully synthesized via the Ugi four-component reaction by treating ferrocenecarboxylic acid with diverse aldehydes, amines, and isocyanides in methanol solution. Their chemical structures were fully characterized by IR, NMR, HR-MS, and X-ray diffraction analyses. They feature unique molecular morphologies and create a 14-membered ring motif in the centro-symmetric dimers generated in the solid state. Moreover, the electrochemical behavior of these ferrocenyl bis-amides was assessed by cyclic voltammetry.

Alternant Bond Distances in Octaethylporphyrin π-Cation Radicals

The possible appearance and nature of alternant bond distance patterns in the inner 16-membered ring of several octaethylporphyrin [Formula: see text]-cation radicals has been investigated. This study was made possible by recognizing an unexpected solvent system, namely dichloromethane/chloroform, even though the [Formula: see text]-cation species have extremely limited solubility in chloroform. A total of six [M(OEP[Formula: see text]][Formula: see text] derivatives were studied by single-crystal X-ray structure determinations. Two new zinc derivatives display, quantitatively, the same alternant pattern observed previously. A new nickel complex shows a smaller but now probably significant alternant pattern. However, a copper derivative, independently analyzed twice, shows no evidence for an alternant pattern. The importance of ring–ring interactions on the energy of the top two orbitals is shown by two distinct magnesium derivatives. The derivative with strongly overlapped rings displays an alternant bond distance pattern, whereas the other, with a modestly overlapped ring pair, does not. This suggests the importance of strong ring–ring interactions in leading to a pseudo-Jahn-Teller state; this hypothesis is also supported by other prior results.

Isomorphous Incorporation of Tin Ions into Germanosilicate Framework Assisted by Local Structural Rearrangement

The crystalline structure of UTL zeolite experienced an unusual orientated collapse and reconstruction within an extremely narrow time window during the structural stabilization process by nitric acid treatment at elevated temperature. Taking full advantage of this unique structural change, extra-large-pore Sn-UTL zeolites were postsynthesized via the reaction between the SnCl4 molecules and the silanols in the hydroxyl nests, which occurred concomitantly with the removal of Ge and/or Si species from the dense layer. The original UTL topology was restored thereafter, leading to a Sn-incorporated analogue. The usage of the most seriously collapsed intermediate structure, which was captured by timing during the precisely controlled acid treatment, was vital for achieving Sn-UTL zeolites with a larger amount of isolated Sn species effectively incorporated. With tetrahedrally coordinated Sn ions in the highly stabilized UTL topology consisting of intersecting 12- and 14-membered ring (MR) pore channels, Sn-UT...

Crystal structure of bis-[μ-1,4-bis-(di-phenyl-phos-phan-yl)butane-κ2P:P']bis-[(3,4,7,8-tetra-methyl-1,10-phenanthroline-κ2N,N')copper(I)] bis-(hexa-fluorido-phosphate) di-chloro-methane disolvate.

The dication of the title compound, [Cu2(C28H28P2)2(C16H16N2)2](PF6)2·2CH2Cl2, has crystallographically imposed inversion symmetry. The copper(I) cation is coordinated in a distorted tetra-hedral geometry by two N atoms of a chelating 3,4,7,8-tetra-methyl-1,10-phenanthroline ligand and two P atoms of two bridging 1,4-bis-(di-phenyl-phosphan-yl)butane ligands, forming a 14-membered ring. An intra-molecular π-π inter-action stabilizes the conformation of the dication. In the crystal, dications are linked by π-π inter-actions involving adjacent phenanthroline rings, forming chains running parallel to [111]. Weak C-H⋯F hydrogen inter-actions are also observed.

Clarithromycin attenuates the expression of monocyte chemoattractant protein-1 by activating toll-like receptor 4 in human mesangial cells.

Signaling pathways induced by the activation of renal toll-like receptor 4 (TLR4) play a pivotal role in chronic kidney disease (CKD). Some recent studies suggested that clarithromycin (CAM), a 14-membered ring macrolide, exerts renoprotective effects by suppressing proinflammatory chemokines. However, its beneficial effects on signaling pathways through renal TLR4 activation are unknown. Cultured human mesangial cells (MCs) were treated with lipopolysaccharide (LPS). Expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleukin-8 (IL-8/CXCL8) was analyzed by quantitative RT-PCR and enzyme-linked immunosorbent assay. Signaling pathways affected by CAM were determined by examining the activation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) by performing western blotting. CAM inhibited both the mRNA and protein expression of MCP-1 without cell injury but did not affect those expressions of IL-8 in LPS-stimulated MCs. Interestingly, CAM decreased p38 MAPK activation by inhibiting phosphorylation but did not affect NF-κB activation. Our results indicated that CAM exerted renoprotective effects by suppression of p38 MAPK activity and by decreasing the expression of MCP-1 in LPS-stimulated MCs. Given the implication of TLR4 signaling in CKD, CAM may be a potential treatment of choice for CKD.

Transformation of erythromycin during secondary effluent soil aquifer recharging: Removal contribution and degradation path

Erythromycin (ERY), a widely used antibiotic, has recently been detected in municipal secondary effluents and poses serious threats to human health during wastewater reusing. In this study, the removal, fate, and degradation pathway of ERY in secondary effluent during soil aquifer treatment was evaluated via laboratory-scale SAT tests. Up to a 92.9% reduction of ERY in synthetic secondary effluent was observed in 1.0m depth column system, which decreased to 64.7% when recharged with wastewater treatment plant secondary effluent. XRD-fractionation results demonstrated that the transphilic acid and hydrophobic acid fractions in secondary effluent compete for the adsorption sites of the packed soil and lead to a declined ERY removal. Moreover, aerobic biodegradation was the predominant role for ERY removal, contributing more than 60% reduction of ERY when recharged with synthetic secondary effluent. Destruction of 14-member macrocyclic lactone ring and breakdown of two cyclic sugars (l-cladinose and d-desosamine) were main removal pathways for ERY degradation, and produced six new intermediates.

A rapid loop-mediated isothermal amplification (LAMP) method for detection of the macrolide-streptogramin type B resistance gene msrA in Staphylococcus aureus.

Macrolide-streptogramin type B resistance (the MSB phenotype) is a multidrug resistance phenotype in Staphylococcus aureus conferred by the resistance gene msrA. However, bacteria having the MSB phenotype are susceptible to lincosamides and 16-membered ring macrolides, which makes profiling resistance genes necessary and urgent for timely and appropriate use of antimicrobials. In this study, the loop-mediated isothermal amplification (LAMP) assay was optimized for prompt detection of the msrA gene. msrA gene sequences were obtained from the National Center for Biotechnology Information (NCBI) database and primers were designed using the LAMP primer designing software PrimerExplorer v.4, which together recognize seven distinct regions of the msrA gene. The specific LAMP primer set designed in this study could amplify the msrA gene within 25min at an isothermal temperature of 62°C. More importantly, the msrA gene could be detected at a sensitivity as low as 100pg. Furthermore, this optimized LAMP assay provided swift detection of the msrA gene even directly from human specimens. In conclusion, this assay may have great clinical application potential for detection of the msrA gene.

Total Synthesis of Putative 11-epi-Lyngbouilloside Aglycon.

We report here the total synthesis of 11-epi-lyngbouilloside aglycon. Our strategy features a Boeckman-type esterification followed by a RCM to form the 14-membered ring macrolactone and a late-stage side chain introduction via a Wittig olefination. Overall, the final product was obtained in 20 steps and 2% overall yield starting from commercially available 3-methyl-but-3-enol. Most importantly, the strategy employed is versatile enough to eventually allow us to complete the synthesis of the natural product and irrevocably confirm its structure.