Current Medicinal Chemistry - Volume 21, Issue 16, 2014

The growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) in and around solid tumors is central to the growth and metastatic spread of cancer. The therapeutic targeting of angiogenesis has become an established modality of cancer treatment, however, more comprehensive targeting of angiogenic signaling pathways may be required to enhance the clinical benefits of this approach. Angiogenesis and lymphangiogenesis are driven, or modulated, by a range of secreted glycoproteins including vascular endothelial growth factors, platelet-derived growth factors, and transforming growth factor-β. These key regulatory growth factors are subject to proteolytic activation, involving highly specific cleavage events, which can occur at the cell surface or in the extracellular milieu. These cleavage events are catalysed by a variety of enzymes including proprotein convertases. This proteolysis can regulate the activity of these growth factors by enhancing binding affinities for cell surface receptors and co-receptors, or by altering their interactions with heparan sulfate proteoglycans, thereby modulating bioavailability. The proteolytic processing of these growth factors complicates strategies for targeting them for diagnostic and/or therapeutic purposes in cancer, as processing can generate various forms with distinct biological properties. Hence it has been important to determine which forms are biologically active for promoting angiogenesis and lymphangiogenesis in cancer, so as to indicate clinical relevance. Here we review the regulation of tumor angiogenesis and lymphangiogenesis by proteolytic activation of growth factors, and the potential therapeutic and diagnostic strategies arising from our understanding of this process.

Research on Hepatitis C Virus inhibitors has dramatically increased during the past few years. Actually, several classes of anti-HCV drugs, including NS3-4A protease inhibitors, NS5B polymerase inhibitors, NS4B protein to RNA binding inhibitors, and multifunctional viral protein NS5A inhibitors, are in different stages of development. The RNA dependent HCV polymerase is considered an irreplaceable target for future HCV therapy on account of a high degree of conservation across the six HCV genotypes, and agents targeting the active site, such as ribonucleoside analogs, may be particularly advantageous having a high barrier to resistance. The purpose of this review is to present highlights of recent developments in the synthesis of anti-HCV ribonucleosides and to discuss the limitations posed by resistance and drug toxicity.

The Keap1-Nrf2-ARE pathway is one of the most important regulators of cytoprotective responses to oxidative and/or electrophilic stresses, which is believed to play a critical role in the development of many diseases, such as cancer, Alzheimer’s, Parkinson’s, and inflammatory bowel disease. Recent research indicates that the modulation of ARE activation via direct inhibition of the Keap1-Nrf2protein-protein interaction has many advantages, particularly the low cytotoxicity, over indirect covalent modulators of Keap1 protein for the discovery of novel small molecule modulators of this pathway. However, most known inducers (e.g., triterpenoids, isothiocyanates and sulfoxythiocarbamates) that activate the ARE system through electrophilic attacks on the cysteine sulfhydryl group of Keap1 also disrupt theKeap1-Nrf2 interaction. The understanding of co-crystal complex of the Keap1-Nrf2 interactionthus provides a structural basis for the rational design of highly potent direct inhibitors. This review summarizes the recent advances in the medicinal chemistry of small-molecule inhibitors in the areas of drug design, structure-activity relationships, and biological and biochemical properties. The peptides designed from DLG and ETGE motifs of Nrf2 protein that binds to Keap1 Kelch domain with promising binding affinities are highlighted. This review also includes recently reported non-peptide inhibitors with moderate inhibition by high-throughput screening. It is clear that further research is required for the discovery of more potent inhibitors.

Indocyanine green (ICG) is a water-soluble anionic tricarbocyanine dye developed during the Second World War that was first approved for clinical use in humans in 1956. The main features of ICG that make it suitable for bioimaging applications are its near infrared absorption and its fluorescence. Although ICG is mainly used for its fluorescence emission properties, it has also been hypothesized that it can serve as a photosensitizer for photodynamic therapy applications, eliciting cytotoxic effects both in vitro and in vivo when used in combination with light at wavelengths in the region of 800-830 nm. Moreover, ICG can be used for hyperthermia of enhanced-photocoagulation of blood vessels treatment. In this paper we have gathered all the available data concerning the use of ICG for different treatments.

Aims: The objective was to study if cationic phosphorus dendrimers can be used as DC-based vaccine or adjuvant in anti-HIV-1 vaccine development when associated with HIV-1 derived peptides. Materials & Methods: The HIVderived peptides uptake in DC and the phenotype of iDC and mDC were studied using Flow Cytometry analysis. Migration of mDC was evaluated by an in vitro chemotaxis assay. Allogenic T-cells proliferative response induced by DC was studied using Flow Cytometry assays. Cytokines production was analysed by Diaclon DIAplex Th1/Th2/Inflammation kit. Results: All phosphorus dendrimers showed the ability to deliver HIV-derived peptides in DC. The phosphorus dendrimers from second and third generations induced important changes in phenotype. Moreover, the treatment of mDC with the second generation dendrimer and derivated dendriplexes modified cellular migratory properties, altered their capacity to stimulate allogenic naïve T cells in vitro and impeded the production of pro-inflammatory cytokines. Conclusions: The phosphorus dendrimers cannot be used as vaccines because they would not have the ability to induce an immune response. The cationic phosphorus dendrimers associated with HIV-derived peptides have the ability to deliver peptides as non-viral vectors. However, there are other potential therapeutic applications of these compounds, for instance as topical antiinflammatory agents, as compounds for allograft rejection or autoimmune diseases and as agents inducing specific tolerance with antigen-loaded DC against allergy reaction. Nevertheless, these applications need to be evaluated.

Cathepsin S (CatS) is one of the 11 cysteine protease cathepsins which are expressed predominantly in antigen presenting cells (APC) namely B cells, macrophages and dendritic cells. CatS has been implicated in a wide range of diseases such as rheumatoid arthritis, multiple sclerosis, neuropathic pain and allergic disorders. In the present study, pharmacophore mapping studies followed by 3D QSAR analysis was undertaken for a large set of 161 molecules reported to be non-covalent binding and non-peptidic inhibitors of CatS. The activity range (IC50) of these compounds was between 2 picomolar to 100 nanomolar. A five point pharmacophore model with three hydrogen bond acceptors (A), one hydrogen bond donor (D) and one hydrophobic (H) group as pharmacophoric features was developed. The generated model showed reasonable predictive power, with a correlation coefficient Q2 of 0.607. The model was further confirmed by an external test-set validation that showed statistically significant parameters r2 value of 0.840with the R2 value of 0.812 and r2 value of 0.530. Validated model was then used to identify six diverse non-peptidic scaffolds from a commercial structure database by the analyses of parameters such as pharmacophore fitness, docking score, interacting amino acids and ADME properties to achieve prototypical lead compounds.