Current Bioactive Compounds - Volume 9, Issue 3, 2013

Peptides and proteins have been known for more than a century, but was only when du Vigneaud published the first synthesis of oxytocin, that the research on bioactive peptides was truly launched. Since then, the scientific progresses in the field have been astonishing and the synthesis of peptides of virtually any size and complexity is now possible. Perhaps the most important milestone was the development of the solid-phase peptide synthesis (SPPS) by Merrifield (1963), to revolutionize the field. In this critic review, we will analyze how the SPPS contributed to widespread the manufacture of peptides as active pharmaceuticals and what will be the challenges of tomorrow in this field.

An efficient and environmentally benign one- pot four-component domino protocol has been presented for the synthesis of structurally diverse spirooxindoles spiroannulated with chromenopyrazolophthalazines, indazolophthalazines and pyranopyrazolophthalazines involving the reaction of phthalic anhydride, hydrazine hydrate, isatins and cyclic ketones in aqueous alcoholic medium (H2O-C2H5OH: v 5:1) using catalytic amount of sulphamic acid.

A modified method for the synthesis of a series of substituted benzenesulfonamides from benzenesulfonylchloride and substituted amines (1:1) in aqueous media have been adopted at controlled pH (8-10). Transition metal complexes of synthesized ligands were also prepared by refluxing ligands and metal salts (2:1) for one hour. The synthesized compounds have been characterized by spectroscopic techniques (FTIR, 1HNMR and mass spectrometry). Synthesized compounds were analyzed for their activity toward acetyl cholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) inhibition, lipoxygenase (LOX) inhibition, antioxidant (DPPH) and antiurease. As regards biological activities of ligands, only N-(2-nitrophenyl) benzenesulfonamide (3) showed appreciated value of IC50= 77.13± 00 μmole against LOX while all metal complexes showed low activities. Cu complex (C-4) showed moderate activity against LOX while all the other metal complexes had no activity against any enzyme at all. Similarly Zn complexes (Z-2 to Z-6) showed little activity against AChE but the ligands showed no significant activity against any other. Metal complexes showed high capacity toward antiurease activity.

The clinically used glitazones for the management of type 2 diabetes mellitus are full agonists of peroxisome proliferator activated receptors (PPAR)-γ and potent insulin sensitizers. Unfortunately, these molecules suffered from various side effects which resulted in their restriction/ban. Various new strategies were, therefore, developed to overcome the existing problems with the full agonists. Among them the development of partial and dual PPAR agonists are some of the important strategies adopted to improve the adverse profiles of the full agonists. In the present study, 11 novel (5Z)-5- [4-(3-phenoxypropoxy)benzylidene]-1,3-thiazolidine-2,4-dione derivatives were designed, synthesized and evaluated for their possible partial and dual agonistic activities using in silico and in vitro methods. The in silico docking and in vitro PPAR-α & γ competitive binding studies confirm the dual binding potential of these molecules. The post docking analysis reveals that the molecules, 4a, 4b, 4c, 4d, 4e, 4h and 4j, exhibit binding modes similar to a full agonist and molecules, 4f, 4g, 4i and 4k, show binding modes similar to a partial agonist of PPAR-γ receptors. On PPAR-α receptors, all the molecules except, 4a and 4g, show binding modes similar to a full agonist, The molecules, 4a and 4g, however, show binding modes similar to that of a partial agonist. Further, in the in vitro 3T3L1 preadipocytes assay, all the molecules promote the adipocyte differentiation confirming their PPAR-γ agonistic activity. These molecules, therefore, show potential to overcome the problems of the clinically used glitazones in the management of type 2 diabetes mellitus.

Fourier transform infrared (FTIR) spectroscopy and especially FTIR spectroscopic imaging are suitable in the plant analysis. With these techniques, a distinction not only of different plant species, but also of various ingredients within a plant is possible. FTIR spectroscopic imaging enables molecular imaging of complex botanical samples and therefore the detection and characterization of the molecular components of biological tissue. Based on the absorption of IR radiation by vibrational transitions in covalent bonds, the FTIR spectroscopic imaging technique offers the major advantage of the acquisition of local molecular expression profiles, while maintaining the topographic integrity of the tissue by avoiding time-consuming extraction, purification and separation steps. In the present study, it is demonstrated that FTIR spectroscopy enables the distinction of various plant species and FTIR spectroscopic imaging combined with chemometric data analysis enables one to gain a more distinct picture concerning morphology and distribution of active ingredients. In addition, initial evaluations of a three-dimensional distribution of ingredients of various plant roots are shown.

Active quassinoids extracted from Brucea javanica seeds were tested for their activities against Tobacco mosaic virus (TMV). Results from activity-guided assays indicated that the compounds can reduce the replication of the virus by up to 98.5% (50 μg/mL). The active quassinoids inhibit the replication of TMV genomic and subgenomic RNAs and the synthesis of TMV coat protein in vivo but did not destroy the integrality of the virus. Structure-activity relationship (SAR) analysis indicated that the positions of the furan ring, the α,β-conjugated ketone, and integrity of the A ring had significant impacts on the antiviral activity of quassinoids.

Cell-cell communication through gap junctions is aberrant or absent in a majority of human cancer cells, compared to cells in corresponding normal tissues. This and other evidence has led to the hypothesis that gap junction channels, comprised of connexin proteins, are important in growth control and cancer progression. The major goal of this ongoing study was to identify bioactive compounds that specifically upregulate gap junction channel-mediated cell-cell communication as potential anti-tumor therapies. Control of cell-cell communication is linked to growth regulatory intracellular signaling pathways; we therefore further aimed to identify signaling pathways modulated by these compounds in order to assess their potential as targeted anti-tumor therapies. Compounds were screened for their ability to upregulate gap junction-mediated cell-cell communication by using a fluorescent dye transfer assay to measure cell-cell communication between tumor promoter-treated astroglial cells or ras-transformed epithelial cells. Western blotting using connexinspecific and phosphorylation site-specific antibodies was used to monitor phosphorylation changes in signaling pathway proteins. Our results identified three compounds that upregulate gap junction-mediated cell-cell communication in our screening assays, chaetoglobosin K(ChK), 4-phenyl-3-butenoic acid (PBA) and the methyl ester of PBA (PBA-Me). Further analyses demonstrated that in tumorigenic cells, ChK downregulates phosphorylation of Akt kinase, an enzyme in the PI3-kinase signaling pathway that is found to be upregulated in a number of human cancers, on a key activation site. However, ChK did not inhibit PI-3 kinase in vitro as did the classic PI-3 kinase inhibitor, Wortmannin. PBA and PBA-Me were found to upregulate phosphorylation of p38 MAPK on a key activation site in tumorigenic cells, which is downregulated in several human cancer cell types. ChK and PBA also decreased activation of SAPK/JNK, another kinase found to be upregulated in a number of human cancers. These studies highlight the potential of monitoring gap junction intercellular communication for identifying experimental anti-tumor compounds.