Nickel Phosphite-Catalyzed Tetradehydro-Diels-Alder Reactions of (E)-3-ene-1,8-diynes.

A nickel-catalyzed tetradehydro-Diels-Alder reaction of (E)-3-ene-1,8-diynes for the preparation of isoindolines, dihydroisobenzofurans, and tetrahydroisoquinolines has been developed. A series of air-stable nickel catalysts were used in this study, including the novel nickel(0)-phosphite catalysts, Ni[P(O-3,5-Me-Ph)3]4, Ni[P(O-1-naphthyl)3]4, and Ni[P(O-2-naphthyl)3]4. To help understand the type of intermediate in the initial cycloisomerization process, the trapping of nickellacycle intermediates with pinacolborane to yield vinyl boronates is also discussed.

Dirhodium-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles to 2,3-Dehydropiperazines.

The dirhodium(II)-catalyzed synthesis of a range of C2-substituted 2,3-dehydropiperazines using 1-mesyl-1,2,3-triazoles and ß-haloalkylcarbamates is reported. The reaction is proposed to proceed through an α-imino rhodium carbene 1,3-insertion into N-H followed by a base-mediated cyclization. C-Substituted dehydropiperazines can also be conducted directly from terminal alkynes in a three-step, one-pot operation, forming the triazole in situ. This methodology has also been expanded to afford several 2,5-disubstituted 2,3-dehydropiperazines as well as a larger 4,5,6,7-tetrahydro-1H-1,4-diazepine derivative.

Similarities and Differences between Crystal and Enzyme Environmental Effects on the Electron Density of Drug Molecules.

The crystal interaction density is generally assumed to be a suitable measure of the polarization of a low-molecular weight ligand inside an enzyme, but this approximation has seldomly been tested and has never been quantified before. In this study, we compare the crystal interaction density and the interaction electrostatic potential for a model compound of loxistatin acid (E64c) with those inside cathepsin B, in solution, and in vacuum. We apply QM/MM calculations and experimental quantum crystallography to show that the crystal interaction density is indeed very similar to the enzyme interaction density. Less than 0.1 e are shifted between these two environments in total. However, this difference has non-negligible consequences for derived properties.

Sucrose fatty acid esters: synthesis, emulsifying capacities, biological activities and structure-property profiles.

The notable physical and chemical properties of sucrose fatty acid esters have prompted their use in the chemical industry, especially as surfactants, since 1939. Recently, their now well-recognized value as nutraceuticals and as additives in cosmetics has significantly increased demand for ready access to them. As such a review of current methods for the preparation of sucrose fatty acid esters by both chemical and enzymatic means is warranted and is presented here together with an account of the historical development of these compounds as surfactants (emulsifiers). The somewhat belated recognition of the antimicrobial, anticancer and insecticidal activities of sucrose esters is also discussed along with a commentary on their structure-property profiles.

High-Pressure-Promoted and Facially Selective Diels-Alder Reactions of Enzymatically Derived cis-1,2-Dihydrocatechols and Their Acetonide Derivatives: Enantiodivergent Routes to Homochiral and Polyfunctionalized Bicyclo[2.2.2]octenes.

cis-1,2-Dihydrocatechols 5 (X = Me and Cl), which are available in the homochiral form through the whole-cell biotransformation of toluene and chlorobenzene, respectively, undergo Diels-Alder cycloaddition reactions with a range of electron-deficient dienophiles at 19 kbar (1.9 GPa). The favored products of such reactions are adducts of the general form 7 and that arise through the operation of a contrasteric or syn-addition pathway. In contrast, the acetonide derivatives of metabolites 5 undergo anti-selective addition reactions under the same conditions and so producing adducts of the general form 11. Bicyclo[2.2.2]octenes 7 and 11, which embody carbocyclic frameworks of opposite enantiomeric form, are useful scaffolds for chemical synthesis. Computational studies reveal that syn-adduct formation is kinetically and normally thermodynamically favored over anti-adduct formation when the free diols 5 are involved, but the reverse is so when the corresponding acetonides participate as the 4π-addend. Furthermore, the reactions become more exothermic as pressure increases while, concurrently, the activation barrier diminishes and at 6 GPa (60 kbar) almost vanishes.

Asymmetric Synthesis and Stereochemical Assignment of 12C/13C Isotopomers.

A synthesis of chiral hydrocarbons having C1 axis and C3 symmetry, which owe their chirality due to asymmetrical distribution of 12C/13C isotopes, is reported. Their absolute configurations assigned using the vibrational circular dichroism technique conform with those deduced from the absolute configurations of the parent α-formyl cyclopropanes.

Enantioselective Synthesis of anti-1,2-Oxaborinan-3-enes from Aldehydes and 1,1-Di(boryl)alk-3-enes Using Ruthenium and Chiral Phosphoric Acid Catalysts.

A cationic ruthenium(II) complex catalyzes double-bond transposition of 1,1-di(boryl)alk-3-enes to generate in situ 1,1-di(boryl)alk-2-enes, which then undergo chiral phosphoric acid catalyzed allylation of aldehydes producing homoallylic alcohols with a (Z)-vinylboronate moiety. 1,2-Anti stereochemistry is installed in an enantioselective manner. The (Z)-geometry forged in the products allows their isolation in a form of 1,2-oxaborinan-3-enes, upon which further synthetic transformations are operated.

Synthesis of Enantiopure C3 -Symmetric Triangular Molecules.

An asymmetric synthesis of C3 -symmetric triangular macrocycles is reported. 1-Methylsulfonyl-4-(4-vinylphenyl)-1,2,3-triazole undergoes a rhodium(II)-catalyzed cyclotrimerization to establish an enantiopure C3 -symmetric triangular macrocycle motif. This method can be applied to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings.

The synthesis and biological activity of novel anthracenone-pyranones and anthracenone-furans.

An efficient and divergent methodology for the synthesis of new anthracenone-pyranones and anthracenone-furans is described. Key reactions discussed in these syntheses include an aldehyde promoted annulation with a ß-keto-sulfoxide, a domino alkyne insertion/carbonylation/Nu-acylation and a DMEDA promoted Castro-Stephens reaction. We also report the in vitro growth inhibition of these compounds in a range of human cancer cells. The natural product BE-26554A displayed good cell growth activity on BE2-C neuroblastoma and SMA glioblastoma cell lines at 0.17 and 0.16µM (GI50), respectively. Of note, were a CF3 functionalised anthracenone 4-pyranone (chromone) derivative 22, and an anthracenone-furan derivative 54 which displayed 0.20µM and 0.38µM growth inhibition, respectively, in the BE2-C neuroblastoma cell line.

Transition Metal-free Methylation of Amines with Formaldehyde as the Reductant and Methyl Source.

A simple transition metal-free procedure using formal dehyde for the N,N-dimethylation and N-methylation of primary and secondary anilines is reported. The reaction showed limitations on sterically hindered and electron-withdrawing anilines, but is successful on amines with electron-donating substituents. Formaldehyde acts as both the reducing agent and the carbon source in the reaction.

Strengthening Molecular Glues: Design Strategies for Improving Thalidomide Analogs as Cereblon Effectors and Anticancer Agents.

In the two decades since a novel thalidomide analog was last approved, many promising drug candidates have emerged with remarkable potency as targeted protein degraders. Likewise, the advent of PROTACs for suppressing 'undruggable' protein targets reinforces the need for new analogs with improved cereblon affinity, target selectivity and drug-like properties. However, thalidomide and its approved derivatives remain plagued by several shortcomings, such as structural instability and poor solubility. Herein, we present a review of strategies for mitigating these shortcomings and highlight contemporary drug discovery approaches that have generated novel thalidomide analogs with enhanced efficacy as cereblon effectors and/or anticancer agents.

Stereoselective synthesis of 2,3-dihydropyrroles from terminal alkynes, azides, and α,ß-unsaturated aldehydes via N-sulfonyl-1,2,3-triazoles.

A stereoselective method for synthesis of trans-2,3-disubstituted 2,3-dihydropyrroles is reported. N-Sulfonyl-1,2,3-triazoles prepared from terminal alkynes generate α-imino rhodium carbene complexes, which when combined with α,ß-unsaturated aldehydes produce trans-2,3-disubstituted dihydropyrroles. The method can be successfully applied to a one-pot process starting from terminal alkynes.

Inspiration from old dyes: tris(stilbene) compounds as potent gram-positive antibacterial agents.

Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 µg mL(-1) and against Staphylococcus spp. with MICs ranging from 2-4 µg mL(-1). The derivative 17 showed increased activity with MICs of 0.06-0.25 µg mL(-1) against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 µg mL(-1) and clindamycin with MICs of ≤0.5 µg mL(-1). As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development.

A general approach to N-heterocyclic scaffolds using domino Heck-aza-Michael reactions.

Palladium-catalyzed domino Heck-aza-Michael reactions for the synthesis of a series of C1-substituted tetrahydro-ß-carbolines, tetrahydroisoquinolines and isoindolines are described. The domino process involves the initial intermolecular Heck reaction of an aryl bromide with an electron deficient alkene, followed by an intramolecular aza-Michael reaction to form the new N-heterocycle in high yield.

In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties.

Advanced stage liver cancer is predominantly treated with the multi-kinase inhibitor sorafenib; however, this therapeutic agent lacks selectivity in its cytotoxic actions and is associated with poor survival outcomes. Herein we report the design and preparation of several thalidomide derivatives, including a variety of novel thioether-containing forms that are especially rare in the literature. Importantly, two of the derivatives described are potent antiproliferative agents with dose-dependent selectivity for tumorigenic liver progenitor cells (LPC) growth inhibition (up to 36% increase in doubling time at 10 µM) over non-tumorigenic cells (no effect at 10 µM). Furthermore, these putative anti-liver cancer agents were also found to be potent inhibitors of tumorigenic LPC migration. This report also describes these derivatives' effects on several key signalling pathways in our novel liver cell lines by immunofluorescence and AlphaLISA assays. Aryl thioether derivative 7f significantly reduced STAT3 phosphorylation (23%) and its nuclear localisation (16%) at 10 µM in tumorigenic LPCs, implicating the IL-6/JAK/STAT3 axis is central in the mode of action of our derivatives.

Domino Heck-aza-Michael reactions: efficient access to 1-substituted tetrahydro-beta-carbolines.

A simple and efficient palladium-catalyzed domino reaction for the synthesis of a series of C1-substituted tetrahydro-beta-carbolines is described. This domino process involves a Heck reaction at the indole 2-position of a halogenated tryptamine precursor, followed by intramolecular aza-Michael addition.

The antiplasmodial activity of norcantharidin analogs.

The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 µM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 µM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 µM, representing a fivefold enhancement over norcantharidin.

Formation and reactions of azepino[4,5-b]indoles: an unprecedented ozone reaction in the formation of novel benzo[c]naphthyridinones.

Herein we report the formation and interesting reactivity of several azepino[4,5-b]indole heterocycles. Initially, a key intramolecular Heck reaction is used to efficiently create the azepino[4,5-b]indole seven membered ring containing an exocyclic double bond. Treatment of the olefin with ozone results in an unprecedented secondary reaction of the Criegee intermediate, through intramolecular olefin trapping, to afford a benzo[c]naphthyridione containing a bridging cyclic peroxide.

Efforts toward elucidating Thalidomide's molecular target: an expedient synthesis of the first Thalidomide biotin analogue.

Herein we describe the synthesis of the first Thalidomide-biotin analogue in order to initiate investigations into the unknown molecular mode of action of Thalidomide. In this manner we describe the attachment of biotin tether through the Huisgen 1,3-dipolar cycloaddition or "click" synthetic methodology.

New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles.

A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFkappaB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.