Current Medicinal Chemistry (v.21, #16)

The growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) in and around solidtumors is central to the growth and metastatic spread of cancer. The therapeutic targeting of angiogenesis has become anestablished modality of cancer treatment, however, more comprehensive targeting of angiogenic signaling pathways maybe 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, involvinghighly specific cleavage events, which can occur at the cell surface or in the extracellular milieu. These cleavage eventsare catalysed by a variety of enzymes including proprotein convertases. This proteolysis can regulate the activity of thesegrowth factors by enhancing binding affinities for cell surface receptors and co-receptors, or by altering their interactionswith heparan sulfate proteoglycans, thereby modulating bioavailability. The proteolytic processing of these growth factorscomplicates strategies for targeting them for diagnostic and/or therapeutic purposes in cancer, as processing can generatevarious forms with distinct biological properties. Hence it has been important to determine which forms are biologicallyactive for promoting angiogenesis and lymphangiogenesis in cancer, so as to indicate clinical relevance. Here we reviewthe regulation of tumor angiogenesis and lymphangiogenesis by proteolytic activation of growth factors, and the potentialtherapeutic and diagnostic strategies arising from our understanding of this process.

Recent Highlights in the Synthesis of Anti-HCV Ribonucleosides by A. Piperno, M. Cordaro, A. Scala, D. Iannazzo (1843-1860).
Research on Hepatitis C Virus inhibitors has dramatically increased during the past few years. Actually, severalclasses of anti-HCV drugs, including NS3/4A protease inhibitors, NS5B polymerase inhibitors, NS4B protein to RNAbinding inhibitors, and multifunctional viral protein NS5A inhibitors, are in different stages of development. The RNAdependent HCV polymerase is considered an irreplaceable target for future HCV therapy on account of a high degree ofconservation across the six HCV genotypes, and agents targeting the active site, such as ribonucleoside analogs, may beparticularly advantageous having a high barrier to resistance. The purpose of this review is to present highlights of recentdevelopments in the synthesis of anti-HCV ribonucleosides and to discuss the limitations posed by resistance and drugtoxicity.

Updated Research and Applications of Small Molecule Inhibitors of Keap1-Nrf2 Protein-Protein Interaction: a Review by Chunlin Zhuang, Zhenyuan Miao, Chunquan Sheng, Wannian Zhang (1861-1870).
The Keap1-Nrf2-ARE pathway is one of the most important regulators of cytoprotective responses to oxidativeand/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 activationvia 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 thispathway. However, most known inducers (e.g., triterpenoids, isothiocyanates and sulfoxythiocarbamates) that activate theARE 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 rationaldesign of highly potent direct inhibitors. This review summarizes the recent advances in the medicinal chemistry ofsmall-molecule inhibitors in the areas of drug design, structure-activity relationships, and biological and biochemicalproperties. The peptides designed from DLG and ETGE motifs of Nrf2 protein that binds to Keap1 Kelch domain withpromising binding affinities are highlighted. This review also includes recently reported non-peptide inhibitors with moderateinhibition by high-throughput screening. It is clear that further research is required for the discovery of more potentinhibitors.

Indocyanine Green: Photosensitizer or Chromophore? Still a Debate by Camille Giraudeau, Albert Moussaron, Aurelie Stallivieri, Serge Mordon, Celine Frochot (1871-1897).
Indocyanine green (ICG) is a water-soluble anionic tricarbocyanine dye developed during the Second WorldWar that was first approved for clinical use in humans in 1956. The main features of ICG that make it suitable for bioimagingapplications are its near infrared absorption and its fluorescence. Although ICG is mainly used for its fluorescenceemission properties, it has also been hypothesized that it can serve as a photosensitizer for photodynamic therapyapplications, eliciting cytotoxic effects both in vitro and in vivo when used in combination with light at wavelengths in theregion of 800-830 nm. Moreover, ICG can be used for hyperthermia of enhanced-photocoagulation of blood vesselstreatment. In this paper we have gathered all the available data concerning the use of ICG for different treatments.

HIV-Antigens Charged on Phosphorus Dendrimers as Tools for Tolerogenic Dendritic Cells-Based Immunotherapy by Enrique Vacas-Cordoba, Hugo Bastida, Marjorie Pion, Aurelien Hameau, Maksim Ionov, Maria Bryszewska, Anne Marie Caminade, Jean Pierre Majoral, Maria-Angeles Munoz-Fernandez (1898-1909).
Aims: The objective was to study if cationic phosphorus dendrimers can be used as DC-based vaccine or adjuvantin anti-HIV-1 vaccine development when associated with HIV-1 derived peptides. Materials & Methods: The HIVderivedpeptides uptake in DC and the phenotype of iDC and mDC were studied using Flow Cytometry analysis. Migrationof mDC was evaluated by an in vitro chemotaxis assay. Allogenic T-cells proliferative response induced by DC wasstudied 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 dendrimersfrom second and third generations induced important changes in phenotype. Moreover, the treatment of mDC withthe second generation dendrimer and derivated dendriplexes modified cellular migratory properties, altered their capacityto stimulate allogenic naïve T cells in vitro and impeded the production of pro-inflammatory cytokines. Conclusions: Thephosphorus 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-viralvectors. However, there are other potential therapeutic applications of these compounds, for instance as topical antiinflammatoryagents, as compounds for allograft rejection or autoimmune diseases and as agents inducing specific tolerancewith 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 antigenpresenting cells (APC) namely B cells, macrophages and dendritic cells. CatS has been implicated in a wide range of diseasessuch as rheumatoid arthritis, multiple sclerosis, neuropathic pain and allergic disorders. In the present study, pharmacophoremapping studies followed by 3D QSAR analysis was undertaken for a large set of 161 molecules reported tobe non-covalent binding and non-peptidic inhibitors of CatS. The activity range (IC50) of these compounds was between 2picomolar to 100 nanomolar. A five point pharmacophore model with three hydrogen bond acceptors (A), one hydrogenbond donor (D) and one hydrophobic (H) group as pharmacophoric features was developed. The generated model showedreasonable predictive power, with a correlation coefficient Q2 of 0.607. The model was further confirmed by an externaltest-set validation that showed statistically significant parameters r2 value of 0.840with the R2p value of 0.812 and r2m valueof 0.530. Validated model was then used to identify six diverse non-peptidic scaffolds from a commercial structure databaseby the analyses of parameters such as pharmacophore fitness, docking score, interacting amino acids and ADMEproperties to achieve prototypical lead compounds.