Rose M. McConnell

POLYFURAN AND CO-POLYMERS: A CHEMICAL SYNTHESIS

The use of conductive polymers as a substitute for metallic conductors and semiconductors has attracted much attention in the literature. In particular, aromatic heterocyclic polymers constitute an important class because they possess chemical and electrical stability. The properties of these polymers are promising for their many technological uses such as antistatic coatings, solar cells, electronic devises, and so on. Polyfuran is among the least common heterocyclic polymers. Polyfuran has been reported to be much less stable that either polypyrrole or polythiophene. The chemical synthesis of polyfuran using a mild oxidizing agent, pyridinium chlorochromate is described. Also, the preparation of ten co-polymers of polyfuran with one to five percent pyrrole or thiophene is reported. The polymers are characterized by 1H NMR, IR, and ESR spectroscopy, and the electrical conductivity of the synthetic polyfuran and ten co-polymers is provided.

New Cathepsin D Inhibitorswith Hydroxyethylamine Isosteres: Preparation and Characterization

The lysosomal aspartyl protease, cathepsin D, has been suggested to play a role in the metastatic potential of several types of cancer. Cathepsin D is secreted by malignant cells, and is believed to be involved in the breakdown of the extracellular matrix. High levels of active cathepsin D have been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Also cathepsin D has recently been associated with the development of Alzheimers disease. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. In the present study twenty-eight compounds containing (hydroxyethyl)amine isosteres with cyclic tertiary amines have been synthesized. These compounds show significant activity as cathepsin D inhibitors, many with IC(50) values in the nanomolar range. For example, the compounds that contain hydroxyethylamines where the amine is formed from N-piperazine-2-carboxylic acid methyl ester, 4y-bb, show IC(50) values ranging from 2.5 to 15 nM.

Synthesis and cathepsin D inhibition of peptide-hydroxyethyl amine isosteres with cyclic tertiary amines

Cathepsin D, a lysosomal aspartic protease, has been suggested to play a role in the metastatic potential of several types of cancer. A high activated cathepsin D level in breast tumor tissue has been associated with an increased incidence of relapse and metastasis. High levels of active cathepsin D have also been found in colon cancer, prostate cancer, uterine cancer and ovarian cancer. Hydroxyethyl isosteres with cyclic tertiary amine have proven to be clinically useful as inhibitors of aspartyl proteases similar to cathepsin D in activity, such as the HIV-1 aspartyl protease. The design and the synthesis of (hydroxyethyl)amine isostere inhibitors with cyclic tertiary amines is described. The IC50 and Ki (app) values for the six cathepsin D inhibitors and pepstatin are reported. Compounds 7b,3(S)-[Acetyl-L-valyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol,and 7c, 3(S)-[Acetyl-L-leucyl-L-phenylalanylamino]-4-phenyl-1-N-piperidine-2(S)-butanol, showed the most potent inhibition of cathepsin D hydrolysis of hemoglobin with IC50 values of 3.5 nM and 4.5 nM, respectively.

Subcloning and Expression of Functional Human Cathepsin B and K in E. coli: Characterization and Inhibition by Flavonoids

1.1 Cathepsins Cathepsins, originally identified as lysosomal proteases, play a fundamental role in intracellular protein turnover in lysosomes. However, several cathepsins and variants of cathepsins can also be found on the cell membrane, in the cytosol, nucleus, mitochondria, and extracellular space. These cathepsins are involved in a variety of important physiological and pathological processes [reviewed in: (Brix et al., 2008; Frlan and Gobec, 2006; Lutgens et al., 2007; Mohamed and Sloane, 2006; Nomura and Katunuma, 2005; Obermajer et al., 2008; Reiser et al., 2010; Stoka et al., 2005; Turk et al., 2001; Vasiljeva et al., 2007; Victor and Sloane, 2007)]. Cathepsins are classified mechanistically into groups which include serine (cathepsins A and G), aspartic (cathepsins D and E), and cysteine cathepsins (cathepsins B, C, F, H, L, K, O, S, V, W, and X). This classification is based on the nucleophilic residues present on their active sites responsible for proteolytic cleavage (Rawlings et al., 2006; Turk et al., 2001). Cathepsins are synthesized as zymogens composed of a signal peptide, a propeptide, and mature protein of distinct length and substrate specificity for individual cathepsins (Rawlings et al., 2006). The signal peptide is cleaved in the Endoplasmic Reticulum and the pro-protein is activated by proteolytic removal of the N-terminal pro-peptide either by autocatalysis in acidic environments, or by other proteases. The pro-peptide region of the cathepsin plays multiple roles. It can act as an inhibitor to block access to the active site that regulates cathepsin activity. In addition the propeptide can act as an intramolecular chaperone that assists in protein folding, or as a trafficking signal that targets the protein to its destination (Turk et al., 2002). Cathepsins exhibit a broad range of functions and tissue expression (Brix et al., 2008; Turk et al., 2001). Some of the cathepsins are ubiquitously expressed and others are tissue or cell-type specific. Cathepsins have been shown to be involved in the process of tumor invasion and metastasis (Bialas and Kafarski, 2009; Lindeman et al., 2004; Nomura and Katunuma, 2005; Obermajer