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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. Host specificity and mutagenesis studies suggest that the helix D region of CD81 mediates binding to HCV-E2. Structural analysis of CD81 has enabled the synthesis of small molecules designed to mimic the space and hydrophobic features of the solvent-exposed face on helix D. Utilizing a novel bis-imidazole scaffold a series of over 100 compounds has been synthesized. Seven related, imidazole-based compounds were identified that inhibit binding of HCV-E2 to CD81. The inhibitory compounds have no short-term effect on cellular expression of CD81 or other tetraspanins, do not disrupt CD81 associations with other cell surface proteins, and bind reversibly to HCV-E2. These results provide an important proof of concept that CD81-based mimics can disrupt binding of HCV-E2 to CD81.

Peptides containing the sequence Arg-Gly-Asp antagonize binding of fibrinogen to its platelet GPIIb/IIIa receptor, thereby inhibiting platelet aggregation. Incorporation of the sequence into cyclic pentapeptide disulfides has been reported to yield effective antagonists. The conformations in solution of two such antagonists, (2-mercaptobenzoy1)-Na-methylArgGly-Asp-2-mercaptoanilide cyclic disulfide (1) and Ac-Cys-Na-methylArg-Gly-A~p-Pen-NH~ cyclic disulfide (2), have been studied using a constrained distance geometry search procedure in conjunction with proton NMR data, and a structure of 1 has been determined from single-crystal X-ray diffraction data. NMR spectra of the cyclic diaryl disulfide 1 at 203 K in methanol show two slowly exchanging conformations. The Arg-Gly-Asp region of the major form is characterized, inter alia, by an extended Gly residue flanked by an Na-methylArg residue in a conformation roughly consistent with the i + 2 position of a &turn and an Asp residue in a C7 like conformation. In the minor component, the Asp residue is near the aR conformation. The bamer to exchange between the two forms is estimated at 11 kcal/mol. NMR data and analysis of the constrained distance geometry search results suggest that, at room temperature in dimethyl sulfoxide-sulfolane, the dominant conformation of the Arg-Gly-Asp regions of both 1 and 2 is like that in the major component of 1 at 203 K. (2-Mercaptobenzoy1)-Na-methylArg-Gly-Asp-2-mercaptoanilide cyclic disulfide (1) was crystallized from aqueous ethanol as a solvated nitrate salt in a cell of dimensions a = 27.919 (16) A, b = 7.552 (3) A, c = 16.3131 (10) A, and j 3 = 108.79 (5)' with four formula units in space group C2. The structure was solved by direct methods and refined to R = 0.057 for 2869 observations (I 2 340). The crystal structure of 1 and the most probable conformation of its minor form in solution agree closely.

Diamide and amide-ester derivatives of imidazole-4,5-dicarboxylic acid form reliable hydrogen-bonding motifs in the solid state. The crystal structures of symmetrically substituted and dissymmetrically substituted diamides as well as amide-ester combinations were analyzed in order to identify the intermolecular hydrogen-bonding patterns. An intramolecular seven-membered hydrogen-bonded conformation forms in all derivatives where the possibility existed due to the functionality present. The motifs observed for the diamides include intermolecular NH···O and NH···N hydrogen-bonded dimers, with the exceptions to these motifs occurring in compounds having benzylamine substituents. The amines with a higher classification (i.e., 3° > 2° > 1°) in the dissymmetrically substituted diamides are the intramolecular hydrogen bond donors in the solid state, consistent with the capacity of the alkyl group to stabilize developing carbocation character resulting from bond polarization. The amide-ester derivatives also form an intramolecular hydrogen bond and an intermolecular motif based on NH···N and two different C2−H···O hydrogen bonds. A pyrrole amide-ester derivative forms an intramolecular NH···O hydrogen bond in the solid state and an intermolecular NH···O hydrogen-bonded chain. With the exception of the benzylamine-substituted diamides, the intermolecular hydrogen-bonded motifs appear reliable for these imidazole-4,5-dicarboxylic acid derivatives and will be useful in the design of analogues for specific applications.

The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG, 1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were observed when Gpp(NH)p was either absent or present, and they were analogous to the effects observed previously for PLG and the PLG peptidomimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the gamma-lactam peptidomimetics of PLG, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, 5 altered apomorphine-induced rotational behavior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.

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. This review focuses on the regulation of FA synthesis in BC cells, and the impact of FA, or the lack thereof, on the tumor cell phenotype. Given growing awareness of the impact of dietary fat and obesity on BC biology, we will also examine the less-frequently considered notion that, in addition to de novo FA synthesis, the lipolytic uptake of preformed FA may also be an important mechanism of lipid acquisition. Indeed, it appears that cancer cells may exist at different points along a “lipogenic-lipolytic axis”, and FA uptake could thwart attempts to exploit the strict requirement for FA focused solely on inhibition of de novo FA synthesis. Strategies for clinically targeting FA metabolism will be discussed, and the current status of the medicinal chemistry in this area will be assessed.