SAR of Novel 3-Arylisoquinolinones: -Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules.

A set of -substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding analogues. These compounds were initially proposed as inhibitors of -ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(-fluorophenyl)isoquinolin-1(2)-one () could mimic colchicine and interact with microtubules, a recognized target for cancer therapy.

Strict conformational demands of RNA cleavage in bulge-loops created by peptidyl-oligonucleotide conjugates.

Potent knockdown of pathogenic RNA in vivo is an urgent health need unmet by both small-molecule and biologic drugs. 'Smart' supramolecular assembly of catalysts offers precise recognition and potent destruction of targeted RNA, hitherto not found in nature. Peptidyl-oligonucleotide ribonucleases are here chemically engineered to create and attack bulge-loop regions upon hybridization to target RNA.

Lead Optimization of Dehydroemetine for Repositioned Use in Malaria.

Drug repositioning offers an effective alternative to drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent inhibitor of the multidrug-resistant strain K1 of (50% inhibitory concentration [IC], 47 nM ± 2.1 nM [mean ± standard deviation]).

Identification of Rare Lewis Oligosaccharide Conformers in Aqueous Solution Using Enhanced Sampling Molecular Dynamics.

Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 μs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms.

Complexes between methyltestosterone and β-cyclodextrin for application in aquaculture production.

The inclusion complexes between 17-α-methyltestosterone (MT) and β-cyclodextrin (bCD) were prepared and characterized in dissolution and solid phase. The complex promoted a sixfold increment in solubility of the hormone. It has a limited solubility and stoichiometry of 2:1 (bCD:MT) determined by DSC, NMR and solubility experiments, the association constant Ka=2846Lmol and complex fraction of 76% (assessed by DOSY-NMR, in (1:3) DMSO/DO).

miRNases: Novel peptide-oligonucleotide bioconjugates that silence miR-21 in lymphosarcoma cells.

MicroRNAs (miRNAs) are active regulators in malignant growth and constitute potential targets for anticancer therapy. Consequently, considerable effort has focused on identifying effective ways to modulate aberrant miRNA expression. Here we introduce and assess a novel type of chemically engineered biomaterial capable of cleaving specific miRNA sequences, i.

'Dual' peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic cleavage of RNA.

Traditional therapeutic interventions against abnormal gene expression in disease states at the level of expressed proteins are becoming increasingly difficult due to poor selectivity, off-target effects and associated toxicity. Upstream catalytic targeting of specific RNA sequences offers an alternative platform for drug discovery to achieve more potent and selective treatment through antisense interference with disease-relevant RNAs. We report a novel class of catalytic biomaterials, comprising amphipathic RNA-cleaving peptides placed between two RNA recognition motifs, here demonstrated to target the TΨC loop and 3'- acceptor stem of tRNA.

Free Energy Calculations using a Swarm-Enhanced Sampling Molecular Dynamics Approach.

Free energy simulations are an established computational tool in modelling chemical change in the condensed phase. However, sampling of kinetically distinct substates remains a challenge to these approaches. As a route to addressing this, we link the methods of thermodynamic integration (TI) and swarm-enhanced sampling molecular dynamics (sesMD), where simulation replicas interact cooperatively to aid transitions over energy barriers.

Exploring protein kinase conformation using swarm-enhanced sampling molecular dynamics.

Protein plasticity, while often linked to biological function, also provides opportunities for rational design of selective and potent inhibitors of their function. The application of computational methods to the prediction of concealed protein concavities is challenging, as the motions involved can be significant and occur over long time scales. Here we introduce the swarm-enhanced sampling molecular dynamics (sesMD) method as a tool to improve sampling of conformational landscapes.

Configuration and conformation of alfentanil hydrochloride. Conformational study by NMR and theoretical calculations.

The configurational and conformational structure of alfentanil hydrochloride (1) was studied by nuclear magnetic resonance and theoretical calculations. Compound 1 is best described by equilibrium between two stereoisomeric piperidinium rings with the N-substituent always being in equatorial position. Nuclear magnetic resonance spectra demonstrate that, depending on the solvent, 1 adopts the conformation with an axial methoxymethylene group.

Secondary structure of short β-peptides as the chiral expression of monomeric building units: a rational and predictive model.

Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The cis-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the trans-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers.

Folding and self-assembling with beta-oligomers based on (1R,2S)-2-aminocyclobutane-1-carboxylic acid.

Improved methodologies are provided to synthesize (1R,2S)-2-aminocyclobutane-1-carboxylic acid derivatives and their incorporation into beta-peptides of 2-8 residues bearing different N-protecting groups. The conformational analysis of these oligomers has been carried out by using experimental techniques along with theoretical calculations. This study shows that these oligomers adopt preferentially a strand-type conformation in solution induced by the formation of intra-residue six-membered hydrogen-bonded rings, affording cis-fused [4.

Molecular tweezers for enantiodiscrimination in NMR: Di-(R,R)-1-[10-(1-hydroxy-2,2,2-trifluoroethyl)-9-anthryl]-2,2,2-trifluoroethyl benzenedicarboxylates.

A series of new chiral molecular tweezers, di-(R,R)-1-[10-(1-hydroxy-2,2,2-trifluoroethyl)-9-anthryl]-2,2,2-trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated.

Size-tunable trehalose-based nanocavities: synthesis, structure, and inclusion properties of large-ring cyclotrehalans.

An efficient strategy toward the synthesis of large-ring cyclodextrin (CD) analogs alternating alpha,alpha'-trehalose disaccharide subunits and pseudoamide segments (cyclotrehalans, CTs), involving a bimolecular macrocyclization reaction as the key step, is reported. NMR and molecular modeling confirmed that the eight and ten alpha-d-glucopyranoside subunits in tetrameric and pentameric CT homologues (CT4 and CT5, respectively) are magnetically equivalent, as in the gamma and epsilonCD counterparts. Yet, the orientation of the monosaccharide constituents is reversed in CTs as compared with CDs, the beta-face being directed to the inside of the nanometric cavity while the alpha-face remains in contact with the bulk solvent.