Organo-catalyzed enantioselective synthesis of some β-silyl γ-alkyl γ-butyrolactones as intermediates for natural products

The enantioselective synthesis of some β-silyl γ-alkyl γ-butyrolactones has been achieved by an organo-catalyzed Michael addition of enolizable aldehydes onto a silylmethylene malonate followed by a silicon-facilitated Bayer–Villiger oxidation of the β-silyl aldehyde adducts as the key step. γ-Alkyl γ-butenolides were obtained from the β-silyl γ-alkyl γ-butyrolactones by Fleming–Tamao oxidation of the silyl group to a hydroxy group and subsequent elimination. These butenolides are the advanced intermediates of some natural products such as (+)-γ-caprolactone, (+)-methylenolactocine, and (?)-quercus lactone.     

NSAID’s and selectively COX-2 inhibitors as potential chemoprotective agents against cancer: 1st Cancer Update

Non-steroidal anti-inflammatory drugs act by inhibiting cyclooxigenase enzyme in the plasma membrane predominantly. Nowadays many researchers have observed a great involvement of these anti-inflammatory drugs in the cure of different types of cancers. This review shows the role of cyclooxigenase inhibitors specifically type-2 in cure or prevention of different types of cancers.     

CH bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

The direct functionalization of C? H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon–carbon and carbon–heteroatom bonds. This Review provides an overview of C? H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.     

Toward the synthesis of γ-pyrone-containing natural products: diastereoselective aldol-type reaction of a γ-pyrone

The diastereoselective aldol-type reaction of a γ-pyrone via a sodium anion has been developed. This reaction is useful for synthesizing γ-pyrone-containing natural products. Also, we applied the Mukaiyama aldol-type reaction of silyl enol ether of γ-pyrone by using TiCl₄. This Mukaiyama aldol-type reaction of γ-pyrone indicated higher anti-aldol selectivity than the aldol-type reaction of a γ-pyrone with NaHMDS.     

Identify promising IKK-β inhibitors: A docking-based 3D-QSAR study combining molecular design and molecular dynamics simulation

Inhibitor of nuclear factor kappa B kinase subunit beta (IKK-β), a specific regulator of nuclear factor-κB (NF-κB), is considered a valid target to design novel drugs to treat rheumatoid arthritis, glomerulonephritis and various cancers. In this study, in order to design and then identify promising compounds targeting IKK-β, a series of reported IKK-β inhibitors were used to develop 3D-QSAR models. Docking-based and minimization-based poses were generated for model construction. CoMSIA model #8 based on docking poses was selected due to its satisfactory internal and external validation results and the sufficient information delivery capability. After a contour map analysis, 41 new designs were depicted based on a graphical design scheme and 25 of them were assessed as eligible for screening. Compound 21MX007 has aroused our attention for its both competitive QSAR-prediction and docking-scoring result. Detailed docking interactions of 21MX007-protein complex were investigated via a deep analysis of docking results and a comparative molecular dynamics simulation. Strong interactions and an extra hydrogen bond which echoes the H-bond requirements of substituent acquired from the design scheme were observed. From MD analysis, 21MX007-protein system was tested. The system was proved to have good stability in terms of a downward trend of RMSD and Rg values and a continuous and stable H-bond interaction and a lower average binding free energy. Thus, compound 21MX007 was successfully identified as a promising IKK-β inhibitor.     

β-Lactam derivatives as enzyme inhibitors: halogenated β-lactams and related compounds

Different modifications of the imine – acyl chloride reaction were used for the synthesis of 3-mono- and 3,3-dihalogenated 1,4-diaryl substituted β-lactams. Furthermore, these β-lactams were modified by halogen substitution either at the aryl at position 1 or at the aryl substituent at position 4, or at both positions. The influence of the halogen atoms on the reactivity of the β-lactam ring, visible by the carbonyl frequence in their IR spectra, was studied. A selection of compounds was tested as inhibitors of the serin protease porcine pancreatic elastase. No simple correlation between IR frequence and biological activity was found. Finally, the base induced rearrangement of N-benzyl β-lactams was used for the synthesis of 4,5-diaryl substituted pyrrolidinones. Correspondence: Hans-Hartwig Otto, Department of Pharmaceutical/Medicinal Chemistry (PMC), Institute of Pharmacy, Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany.     

Asymmetric synthesis of heteroorganic analogs of natural products. 6. (S)-α-amino-ω-phosphonocarboxylic acids

Alkylation, by -haloalkylphosphonates, of the Ni(II) complex of the Schiff base formed from glycine and (S)-2-N-(N¹-benzylprolyl)-o-aminobenzophenone has been used for the asymmetric synthesis of (S)-2-amino-4-phosphonobutyric and (S)-2-amino-5-phosphonovaleric acids.Institute of Bioorganic Chemistry and Oil Chemistry, Ukrainian Academy of Sciences, 250800 Kiev. A. N. Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences, 117813 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 2, pp. 397–402, February, 1992.     

Different stapling-based peptide drug design:Mimicking α-helix as inhibitors of protein-protein interaction

We category and analyze key examples of various peptide stapling strategies based on different cross-links aligned on the side chain of peptides mainly in the last three years.     

From toluene to triquinanes: formal total syntheses of the sesquiterpenoid natural products (−)-hypnophilin and (−)-coriolin

The enantiomerically pure cis-1,2-dihydrocatechol 6, which is readily obtained via the whole-cell biotransformation of toluene, has been converted into the linear triquinane 3 using a reaction sequence involving Diels–Alder cycloaddition and oxa-di-π-methane rearrangement reactions as key steps. Compound 3 is an advanced intermediate associated with several previously reported total syntheses of the sesquiterpenoid natural products (?)-hypnophilin (1) and (?)-coriolin (2). Related chemistry has provided the tetracyclic compound 5, another established precursor to (?)-coriolin (2).     

Structure–activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4), which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenyl-ether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure–activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental k _i data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier (e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO₂ group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors.     

One-pot regio- and stereoselective synthesis of α'-methoxy-γ-pyrones: biological evaluation as mitochondrial respiratory complex inhibitors

The one-pot construction of functionalized α'-methoxy-γ-pyrones is detailed. Starting from α,α'-dimethoxy-γ-pyrone, molecular diversity is attained by a regio- and stereoselective desymmetrization using allyllithium followed by vinylogous aldol reaction. Mechanistic considerations including density functional theory calculations and insightful experiments have been gathered to shed light on this complex multistep process. To illustrate the versatility of this methodology, some of the molecules prepared were evaluated for their ability to inhibit NADH-oxidase and NADH-ubiquinone oxidoreductase. In the process, a potent new inihibitor of NADH-oxidase activity (IC(50) 44 nM) was identified.     

Synthesis of aryl substituted quinones as β-secretase inhibitors: Ligand-free direct arylation of quinones with aryl halides

The simple ligand-free direct arylation of quinones with aryl halides applying Pd(OAc)₂ as a catalyst in accordance with Heck reaction was studied. This reaction provided a simple and efficient synthetic approach to efficient inhibitors of β-secretase aryl-substituted quinones.     

Ligand-observed in-tube NMR in natural products research: A review on enzymatic biotransformations,protein–ligand interactions,and in-cell NMR spectroscopy

Natural product-observed NMR methods have considerably expanded the potentialities for in-tube NMR monitoring of complex enzymatic biotransformations and investigation of protein-natural product interactions even in living cells. We review, herein, the significant advantages of ligand-observed in-situ NMR monitoring of enzymatic biotransformations without restoring to laborious and time-consuming chromatographic methods. Emphasis will be given to the potentialities of the use of the NMR bioreactor: (i) to investigate through saturation transfer difference (STD), the capacity of natural products to serve as enzyme substrates, (ii) to monitor multiple biotransformation products of natural products with the use of immobilized enzymes and (iii) to investigate interactions of biotransformed products with protein targets. The use of STD and its variants, transfer effect Noes for PHArmacophore Mapping (INPHARMA) NMR, in conjunction with computational methods, can provide excellent tools in investigating competitive binding modes even in proteins with multiple binding sites. The method has been successfully applied in the study of unsaturated free fatty acids (UFFAs)-serum albumin complexes in which the location and conformational states of UFFAs could not be determined accurately, despite numerous X-ray structural studies, due to conformational averaging. This combined method, thus, may find promising applications in the field of protein-natural product recognition research. The emerging concept of in-cell NMR and recent applications will be discussed since they can provide atomic level insights into natural product-protein interactions in living cells without the need of isotope labelled techniques.     

(S)-ABOC: a rigid bicyclic β-amino acid as turn inducer

In order to investigate the ability of the (S)-aminobicyclo[2.2.2]octane-2-carboxylic acid 1 (H-(S)-ABOC-OH) to induce reverse turns into peptides, two model tripeptides, in which this bicyclic unit was incorporated into the second position, were synthesized and analyzed by FT-IR, CD, NMR, and X-ray studies.     

l-Threonine-catalysed asymmetric α-hydroxymethylation of cyclohexanone: application to the synthesis of pharmaceutical compounds and natural products

l-Threonine has been found to be an efficient catalyst for the asymmetric α-hydroxymethylation of cyclohexanone with formalin. Reducing the amount of water in the reaction by the addition of magnesium sulfate as a dehydrating additive significantly improves the yield. Applications of (S)-2-hydroxymethyl cyclohexanone and the chiral building blocks derived therefrom for the synthesis of pharmaceutical compounds and natural products have been explored.     

Chalcone derivatives as novel,potent and selective inhibitors against human Notum: Structure–activity relationships and biological evaluations

Human Notum(hNotum) inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer. Herein, two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors. Structure–activity relationship(SAR) studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect, while 4’-ethoxyl and 3’-alkyl substitutions on B-ring were beneficial for hNotum inhibition. Among al...     

Novel sulfonamide-functionalized arylidene indolones as potent α-glucosidase inhibitors: Synthesis,characterization, and in vitro and in silico studies

3-Arylidene-1-(2,6-dichlorophenyl)indolones and in particular their 5-methylaminosulfonyl derivatives efficiently inhibit α-glucosidase enzyme. The results are corroborated by in silico docking studies which show the binding of aminosulfonyl derivatives to be more favorable due to additional hydrogen bonding. The most active compound of the series shows the IC₅₀ of 6.19 μm.