Current Medicinal Chemistry (v.20, #24)

Alzheimer?s Disease and Antioxidant Therapy: How Long How Far? by J. Teixeira, T. Silva, P. B. Andrade, F. Borges (2939-2952).
Alzheimer?s disease (AD) has become a health problem to societies worldwide affecting millions of people.AD normally ensues in middle and late life but its specific cause remains unknown. Besides amyloid-β deposition and hyperphosphorylatedtau protein, increased production of reactive species (RS) has also been described to be a hallmark inearly steps of this disorder. Antioxidant therapy has received considerable attention over the last years as a promising approachto delay or slow the neurodegeneration progression in AD either by boosting the pool of endogenous antioxidants(e.g.vitamins, coenzyme Q10 or melatonin) or by the intake of dietary antioxidants, such as phenolic compounds of flavonoidor non-flavonoid type. However, the majority of antioxidants studied so far have limited success in clinical trials, afact that could be related to their poor distribution and with the inherent difficulties to cross the blood brain barrier and attainthe target sites. Despite the evidence that different classes of antioxidants are neuroprotectants in vitro, the clinicaldata is not consistent. Alzheimer?s disease and antioxidant therapy is still an open question: the research is far from theend but the success may not be so time-consuming if the data obtained so far are gathered and rationally analyzed eitherby checking new targets or by the obtention of new and effective compounds, for instance by the rational modification ofthe previous ones.

n-3 Fatty Acids: Role in Neurogenesis and Neuroplasticity by R. Crupi, A. Marino, S. Cuzzocrea (2953-2963).
Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C)starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately,mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionallyimportant polyunsaturated n—3 fatty acids, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and antiapoptoticeffects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurologicaldiseases. aged or damaged neurons and in Alzheimer?s disease. Their effect in cognitive and behavioral functions andin several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus,is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalianbrain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood andchronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associatedwith cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulatessynaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review theeffect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a newtherapeutic approach for neurodegenerative diseases is pointed out.

For many years the spotlight in drug discovery has been on a relatively small number of validated therapeutictarget classes, such as G-protein coupled receptors and enzymes such as protein kinases, with well characterized enzymaticand cellular activities. However, with recent progress in genomics and proteomics, protein-protein interactions(PPIs) provide new way of finding novel bioactive molecules acting on their interfaces. This review addresses the currentcase studies and state of the art in the development of small chemical modulators controlling interactions of proteins thathave pathological implications in various human diseases and in particular in cancer. The attention is focused on Bcl-2family protein modulators ranging from natural products to synthetic ones with particular interest in foldamers as BH3 alphahelix mimetics.

Human Galectin-3 Selective and High Affinity Inhibitors. Present State and Future Perspectives by R. Tellez-Sanz, L. Garcia-Fuentes, A. Vargas-Berenguel (2979-2990).
Over the last decade an increasing number of studies have been published reporting on the inhibitory potencyor selectivity that several types of ligands show against human galectin-3 (hGal-3). The reason for this interest lies in themany important roles galectins play both in intra and extra-cellular functions. Among galectins, galectin-3 stands out becauseit is the only known member of its subfamily in mammals, is small and monomeric but capable of aggregating, andis known to be involved in a large number of disease processes, from cancer to heart failure. These characteristics androles make hGal-3 an ideal target for drugs. Since it binds β-galactosides, like the rest of the galectin family of proteins,the search and design of potent and at the same time selective inhibitors for it is not an easy task. Herein we discuss thechemical features of the most potent inhibitors described so far, as well as the structural basis of their exhibited selectivity,in order to shed light on the rational design of drugs against this target.

Nowadays, cancer treatment is moving away from conventional cytotoxic drugs to target-based agents. This isprimarily attributed to some remarkable leaps made in deciphering the tumor-relevant signaling pathways. Among them,PI3K/Akt/mTOR cascade presently elicits a substantial amount of pharmaceutical interests owing to its intimate role intumor initiation and progression. Additionally, its medicinal potential lies in some protein kinases along the cascade, embracingPI3K, Akt and mTOR, which regulate crucial cellular activities. During the pursuit of PI3K axis inhibitors, medicinalchemistry efforts have diverged into three separate directions for addressing the issues associated with pioneeringPI3K axis inhibitors, including poor pharmacokinetic (PK) profiles, low kinase specificity and lack of multiple inhibitoryactivities. Distinguished from other reviews in the literature, this article will outline these issues in sequence and give anaccount of recent medicinal chemistry efforts along with updated strides in surmounting them. Particularly, some candidatesdeveloped upon these efforts will be highlighted for their design rationale, preclinical performance or clinical status.Rather than merely focus on stunning breakthroughs, the review will critically remind us of the underlying challenges indeveloping PI3K axis modulators to direct the future research in this field.

Drug-Induced Liver Injury: Mechanisms, Types and Biomarkers by M. Vinken, M. Maes, T. Vanhaecke, V. Rogiers (3011-3021).
Drug-induced liver injury is a ubiquitous issue in clinical settings and pharmaceutical industry. Hepatotoxicityelicited by drugs may be intrinsic or idiosyncratic, both which are driven by different molecular mechanisms. Recently, aunifying mechanistic model of drug-induced liver injury has been introduced. According to this model, drug-induced hepatotoxicityrelies on 3 consecutive steps, namely an initial cellular insult that leads to the occurrence of mitochondrialpermeability transition, which in turn ultimately burgeons into the onset of cell death. Clinically, drug-induced liver injurycan be manifested in a number of acute and chronic conditions, including hepatitis, cholestasis, steatosis and fibrosis.These pathologies can be diagnosed and monitored by addressing well-established physical, clinical chemistry and histopathologicalbiomarkers. In the last few years, several novel read-outs of drug-induced liver injury have been proposed,involving genetic, epigenetic, transcriptomic, proteomic and metabolomic parameters. These new concepts and recent developmentsin the field of drug-induced liver injury are revised in the current paper.

Neurotrophin-3 Stimulates Migration of Mesenchymal Stem Cells Overexpressing TrkC by Y.F. Chen, X. Zeng, K. Zhang, B.Q. Lai, E.A. Ling, Y.S. Zeng (3022-3033).
Background and Purpose: Transplantation/infusion of mesenchymal stem cells (MSCs) is a promising new approachfor treatment of spinal cord injury (SCI). Considering some defined chemokines of MSCs that may have adverseside effects in SCI repair, it is therefore desirable to search for a new chemokine, which should not only be harmless to thehost, but also would attract more MSCs to the injury area of spinal cord. This study sought to demonstrate if neurotrophin-3 (NT-3) would attract migration of MSCs with overexpressing tyrosine kinase C (TrkC) a NT-3 receptor. ExperimentalApproach: A micropipette containing NT-3 was placed in cell culture dish. After this, movement of TrkC gene modifiedMSCs was monitored for 240 min under an inverted microscope equipped with an imaging system. In vivo, a gelatinsponge scaffold containing TrkC gene modified MSCs was transplanted into the injury area of transected rat spinal cord.Following this, replication-deficient recombinant adenoviral vectors carrying human NT-3 gene (Ad-NT-3) was injected 1mm caudal to the transplantation site to create an NT-3 enriched area. Key Results: The results showed that TrkC overexpressingMSCs migrated actively towards the source of NT-3 in the NT-3+TrkC-GFP-MSCs group in vitro. A similarphenomenon was not observed in the control groups. In vivo, transplanted MSCs overexpressing TrkC migrated into theNT-3 enriched area. The incidence of migrating MSCs as well as migration distance was significantly higher than the controlgroups. Conclusion and Implications: The present results suggest that NT-3 may play a role in attracting MSCs withits high affinity for TrkC as a chemokine receptor.