Current Medicinal Chemistry - Volume 21, Issue 28, 2014

Chemotherapy continues to be the main treatment option for cancer. Although systemic chemotherapy can efficiently eradicate cancer cells, a significant proportion of patients carry tumors that present a chemoresistant phenotype, resulting in disease progression, cancer relapse, and reduced survival. It has also become clear that the effect of most chemotherapeutic drugs is associated with their capacity to generate reactive species (RS) that bind to specific structures within the cancer cell and promote cell death. Due to repeated exposure to chemotherapeutic agents, the redox homeostasis of cancer cells is continuously disturbed, which can result in changes to the cell’s ability to cope with excessive RS levels through the production of protective molecules. It is thought that the imbalance resulting from this process— oxidative stress—is toxic to cancer cells. Paradoxically, the metabolites produced during oxidative stress can favor the survival of some cancer subpopulations, which present specific gene signatures that confer a chemoresistant phenotype on these clones. Despite the huge amount of information generated by currently available technologies, we cannot predict whether this resistance will arise during chemotherapy and we still do not fully understand the mechanism by which it arises. In this review, we discuss the main findings regarding the role of oxidative stress signaling in cancer chemotherapy and the key redox molecules and pathways that lead to the development of chemoresistance.

Numerous basic-helix-loop-helix (bHLH) transcription factors (TF) have been found to play important roles in tumor growth and progression. Elucidation of the common features of these TFs can pave the road to possible therapeutic intervention. The existing studies of possible inhibition of these TFs are concentrated on the development of peptides or small molecules that inhibit their dimerization or prevent their DNA binding. The bHLH TFs have striking similarity in many functionally important regions, such as the helical regions of TFs that interact with each other during dimerization and have complementary sets of residues on both sides of a dimer. These are hydrophobic residues along with anionic and cationic residues with complementary charges. Such complementarity also exists in other contact regions of the bHLH TFs. They also have a very specific set of positively charged residues on the surface, which would contact DNA. Such specificity defines a common concept for an in silico design of bHLH TFs inhibitors for a number of existing and important cancer-related TFs.

Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy.

About 2.3% of the world’s population is infected with hepatitis C virus (HCV) and patients have a high risk of developing liver cirrhosis and its complications. Current therapeutic strategies are based on a combination of pegylatedinterferon, ribavirin and (only for patients with genotype 1 infection) a protease inhibitor (boceprevir or telaprevir). Consequently, all these combinations have the limitations of interferon. In fact, they are contraindicated in decompensated disease and in subjects with severe comorbidities, and are associated with a high rate of side effects. Moreover, they are poorly effective in advanced disease. As complete viral eradication is associated with improved disease-free survival, several molecules are under clinical development for their potential to overcome the drawbacks of currently available treatments. This review focuses on the pharmacodynamics, pharmacokinetics, safety and tolerability of ABT-450, a potent inhibitor of non-structural 3 protease. ABT-450 is a substrate of cytochrome P450; hence its co-administration with ritonavir, a cytochrome P450 inhibitor, dramatically increases the plasma concentration and half-life of ABT-450 and allows once-daily administration. Given in monotherapy for 3 days at different doses, ABT-450 causes a mean maximum viral decline of about 4 logs. Interestingly, high doses of ABT-450 are associated with a reduced and delayed development of resistance-conferring mutations. Given in combination with other direct antiviral drugs, the sustained response rate reaches 90-95% in both naïve and treatment-experienced genotype 1 patients, and tolerability is good. In conclusion, ABT-450 is an excellent component of interferon-free combinations for the treatment of chronic HCV infection.

Since Bortezomib was approved by US FDA as the first drug to treat multiple myeloma, various boronic acid compounds have been developed as enzyme inhibitors. This paper reviewed the progress of boronic acid-based inhibitors against enzymes including proteasome, serine protease, HDACs and other enzymes in the past decade.

Src family kinases (SFKs) are a group of non-receptor tyrosine kinases whose activity is involved in the regulation of cellular morphology, motility, proliferation and survival. An aberrant activation and expression of these kinases contribute to the pathogenesis and progression of a broad range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. The search for SFK inhibitors is therefore a promising research topic in medicinal chemistry. Computational studies such as receptor-based and/or ligand-based virtual screening, docking, and molecular modeling proved to be a powerful tool for identifying new SFKs inhibitors. In this review we report and analyze the main examples of computational approaches that allowed the identification of new SFKs ligands and the optimization of either activity and pharmacokinetic profile of lead compounds.

4-Aminobutyric acid is an inhibitory neurotransmitter involved in the control of neuronal activity in the mammalian central nervous system. There is considerable direct and indirect evidence that impaired activity of GABAmediated inhibitory synapses may be an important causative factor in experimental and clinical seizure disorders. This review is focused on the recent development of compounds which can influence GABA neurotransmission by affecting the GABA receptors, the plasma-membrane GABA transporters (GATs) and catabolic enzyme GABA-transaminase (GABAT). These compounds have been primarily investigated in relation to epilepsy, but it has also been found that a decrease in GABA neurotransmission appears to be involved in the aetiology of several neurological disorders such as insomnia, spasticity, neuropathic pain, anxiety and other mental disorders.

This invited review on the beneficial effects of nutraceuticals in the gastrointestinal tract reports previous work conducted by the authors as well as the work by other researchers in this expanding field. The text of our article on several occasions reports sentences very similar or identical to those which appear in the manuscript from which the information was obtained and this applies to both our own work and some other researchers’ work. This was mainly due to the fact that we tried to maintain unchanged the original meaning of what we reported in our review. Also, it was our intention to give full credit to the authors of manuscripts dealing with the gastrointestinal effects of nutraceuticals and in some instances we preferred to quote the original paper rather than the review where this original information was taken from. We realize that a number (8) of manuscripts, source of the information reported in our review, were not included in the reference list (which contains over 100 references) and we deeply apologize for this with the authors of the missing references. In most of the cases this was due to a mistake in the final editing of the manuscript. In some other cases this was because we tried not to exceed the number of references requested. We therefore, by means of this addendum, would like to add to the reference list taken out the articles which were not quoted in the manuscript at the time it was published. Two of the articles deal with the effect of nutraceuticals in the upper gastrointestinal tract. The remaining six deal with the effect of nutraceuticals in the lower gastrointestinal tract.