An insect antifreeze protein from Anatolica polita enhances the cryoprotection of Xenopus laevis eggs and embryos.

Cryoprotection is of interest in many fields of research, necessitating a greater understanding of different cryoprotective agents. Antifreeze proteins have been identified that have the ability to confer cryoprotection in certain organisms. Antifreeze proteins are an evolutionary adaptation that contributes to the freeze resistance of certain fish, insects, bacteria and plants.

An Inhibitor of Fatty Acid Synthase Thioesterase Domain with Improved Cytotoxicity against Breast Cancer Cells and Stability in Plasma.

It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds.

Inhibition of Tetrahydrofuran Hydrate Formation in the Presence of Polyol-Modified Glass Surfaces.

Glycerol was conjugated to glass test tube surfaces in four configurations by employing two different silane spacers, covalent attachment to glycerol at either the 1- or the 2-position, and with a succinic acid spacer. The resulting surfaces were tested for their ability to inhibit the nucleation of tetrahydrofuran hydrate (THF hydrate) in comparison with polyvinylpyrrolidone (PVP), a known polymeric inhibitor of THF hydrate formation. Contact angle measurements were used as an indication of surface modification throughout the glass derivatization steps.

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered.

Brisk fatty acid (FA) production by cancer cells is accommodated by the Warburg effect. Most breast and other cancer cell types are addicted to fatty acids (FA), which they require for membrane phospholipid synthesis, signaling purposes, and energy production. Expression of the enzymes required for FA synthesis is closely linked to each of the major classes of signaling molecules that stimulate BC cell proliferation.

Parallel synthesis of peptide-like macrocycles containing imidazole-4,5-dicarboxylic acid.

We prepared a series of peptide-like 14-membered macrocycles containing an imidazole-4,5-dicarboxylic acid scaffold by using known coupling reagents and protecting group strategies. Yields of the purified macrocycles were poor on average, yet seemingly independent of amino acid substitution or stereochemistry. The macrocycles retain some level of conformational variability as observed by both molecular modeling and X-ray crystallography.

Is RORγ a therapeutic target for treating Mycobacterium tuberculosis infections?

A link is hypothesized between inhibition of the retinoic acid receptor-related orphan receptor γ (RORγ) and treatment of Mycobacterium tuberculosis (Mtb) infection. An unexpected overlap was found between inhibitors of both Mtb H37Rv with RORγ in PubChem. Since RORγ is not present in Mtb, a commonality was reasoned to be cholesterol.

Parallel synthesis of an oligomeric imidazole-4,5-dicarboxamide library.

A library of oligomeric compounds was synthesized based on the imidazole-4,5-dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids. The final compounds incorporate nonpolar amino acids (Leu, Phe, Trp), polar amino acids (Ser, Asp, Arg), and neutral amino acids (Gly, Ala), and were designed to be useful in screening for inhibitors of protein-protein interactions. Many of the protected and deprotected oligomers show evidence of conformational isomers persistent at room temperature in aqueous solution.

Parallel synthesis of a library of symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides bearing amino acid esters.

The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters to afford symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides with intramolecularly hydrogen bonded conformations that predispose the presentation of amino acid pharmacophores. In this work, a total of 45 imidazole-4,5-dicarboxamides bearing amino acid esters were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm.

Parallel synthesis of an imidazole-4,5-dicarboxamide library bearing amino acid esters and alkanamines.

The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters and alkanamines to afford compounds with intramolecularly hydrogen bonded conformations that mimic substituted purines and therefore are hypothesized to be potential inhibitors of kinases through competitive binding to the ATP site. In this work, a total of 126 dissymmetrically disubstituted imidazole-4,5-dicarboxamides with amino acid ester and alkanamide substituents were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm.

Imidazole-4,5-dicarboxamide derivatives with antiproliferative activity against HL-60 cells.

A series of N,N'-disubstituted imidazole-4,5-dicarboxamides (I45DCs) were prepared and tested in order to determine their antiproliferative activity against HL-60 cells. The design of the I45DCs was based in part on the structures of trisubstituted purines complexed with cyclin dependent kinase 2 (cdk2), a protein important in regulating the G1/S transition in the cell cycle, and the intramolecular hydrogen bond in I45DCs that predisposes the conformation to one that mimics substituted adenosines. A majority of the I45DCs in this study inhibit proliferation of HL-60 cells as measured by an MTS mitochondrial functional assay with IC50's in the 2.

Intramolecular hydrogen bond strength and pK(a) determination of N,N'-disubstituted imidazole-4,5-dicarboxamides.

N,N'-Disubstituted imidazole-4,5-dicarboxamides (I45DCs) form an intramolecular hydrogen bond worth an estimated 14 +/- 1 kcal/mol, as measured with a model structure in DMSO-d6 at 3 mM, thereby predisposing the molecular conformation to a folded rather than extended form. The I45DCs also show evidence of aggregation in both CDCl3 (>1 mM) and DMSO-d6 (>10 mM) solutions. These compounds are uncharacteristically weak bases in comparison with imidazoles bearing similar electron-withdrawing groups.

Synthesis of symmetric bis(imidazole-4,5-dicarboxamides) substituted with amino acids.

A series of symmetric bis(imidazole-4,5-dicarboxamides) (bis-I45DCs) were prepared with amino acid esters and a variety of linker groups. The critical pyrazine intermediates, substituted with amino acid esters, were synthesized by stoichiometric control of the amino acid ester, even though primary alkanamines, in comparison, generally offer less selectivity for this reaction. Diamines are added to subsequently react with and open the remaining acyl imidazole bonds in the pyrazine intermediates and thereby yield the bis-I45DCs.

Expected and unexpected results from combined beta-hairpin design elements.

A model beta-hairpin dodecapeptide [EFGWVpGKWTIK] was designed by including a favorable D-ProGly Type II' beta-turn sequence and a Trp-zip interaction, while also incorporating a beta-strand unfavorable glycine residue in the N-terminal strand. This peptide is highly folded and monomeric in aqueous solution as determined by combined analysis with circular dichroism and 1H NMR spectroscopy. A peptide representing the folded conformation of the model beta-hairpin [cyclic(EFGWVpGKWTIKpG)] and a linear peptide representing the unfolded conformation [EFGWVPGKWTIK] yield unexpected relative deviations between the CD and 1H NMR spectroscopic results that are attributed to variations in the packing interactions of the aromatic side chains.

Small molecule inhibition of hepatitis C virus E2 binding to CD81.

The hepatitis C virus (HCV) is a causal agent of chronic liver infection, cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. CD81 is a receptor for HCV envelope glycoprotein E2. Although the binding of HCV-E2 with CD81 is well documented the role of this interaction in the viral life cycle remains unclear.

An improved method for the synthesis of dissymmetric N,N'-disubstituted imidazole-4,5-dicarboxamides.

Symmetrically and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) have diverse bioactivities and therefore represent useful small molecules for lead structure identification in drug discovery. For this reason, an improved synthesis was developed as a first step in the preparation of greater numbers of analogues. The method involves the transformation of imidazole-4,5-dicarboxylic acid into dissymmetrically disubstituted I45DCs in four steps and in a minimum yield of 51%.

Solution and solid-state models of peptide CH...O hydrogen bonds.

Fumaramide derivatives were analyzed in solution by (1)H NMR spectroscopy and in the solid state by X-ray crystallography in order to characterize the formation of CH...