Mini Reviews in Medicinal Chemistry - Volume 12, Issue 5, 2012

If improvements in the quality of human life are to be made in the 21st century it will require the development of new therapeutic technologies that includes the prevention of cognitive aging, Alzheimer's disease [AD] and brain disorders. The task is enormous as there are very few potent drugs for brain diseases/disorders available on the market today. AD is one of the most challenging threats to human health in our society and is unprecedented since the entire aging population will experience neuronal withering and may become the target for treatment. A major characteristic of Alzheimer's disease (AD) pathology is formation of amyloid plaques from aggregation of the amyloid beta peptide. The therapeutic agents that are currently available for AD including acetylcholinesterase inhibitors (AchEIs) and the N-methyl-D-aspartate (NMDA) antagonist are focused on improving the symptoms and do not curb/prevent the progression of the disease. This Anti Alzheimer Agents special issue includes a contribution elaborating the in vitro and in vivo function of a selective acetylcholinesterase inhibitor that when activated releases an active metal chelator for Fe, Cu, Zn ions with neuroprotective activity and inhibiting beta amyloid aggregation. Another contribution features the significant advances made regarding the nature of peptide inhibitors of Aâ having therapeutic application in AD animal models or human clinical trials by binding to amyloid type proteins to prevent amyloid aggregation. Multicomponent medicines derived from plant secondary metabolites potentially could provide significant combination therapies that impact multiple AD pharmacological targets and exert clinical efficacy beyond the reach of small molecule pharmaceuticals. Plants have always relied on mixtures of biologically active molecules to defend themselves against diseases and predation, drug combination therapies are gaining popularity. Traditional Chinese medicine is much more focused on the application of dietary and herbal product mixtures with all their complex interactions, for disease prevention and treatment. Multi-constituent and multifunctional herbs are considered a better therapeutic strategy to prevent or control complex diseases than single active ingredient pharmaceuticals. On this theme the scientific evidence of four of the most frequently used Chinese herbs for dementia treatment is presented. The general availability of green tea makes it an attractive chemopreventive vehicle for disease treatment and health promotion. Therefore the redox responsiveness and amyloid protein perturbation potential of green tea polyphenols are reviewed. The pharmacological activities of plants often appear to reflect their uses in traditional medicine. The ethnopharmacological approach for selecting plants to investigate for the treatment of a particular disease is a relatively successful method for the identification of plants and compounds that may be exploited, for use therapeutically in neurodegenerative and other cognitive disorders....

chelators hold great promise as disease-modifying drugs for Alzheimer’s therapy, and recent research efforts have focused on designing multi-target chelators with increased targeting and efficacy through rational drug design. In this review, we discuss our research studies on the rational design of new multi-target chelators with the potential not only to simultaneously modulate several disease-related targets, but also contain features designed to improve the BBB permeability, increase the brain targeting, and minimize potential side effects. These new chelators include neuroprotective chelators with brain selective monoamine oxidase (MAO) A/B inhibitory activity, acetylcholinesterase (AChE) inhibitors with site-activated chelating and neurogenesis activity, and AChE-MAO A/B inhibitors with siteactivated chelating and neurogenesis activity.

In the last twenty years a considerable body of information has accumulated on the chemical constituents of Chinese herbs and their therapeutic potential. Our evaluation/systematic review [1, 2] of well-designed, randomized double blind controlled trials on Chinese herbal medicines beneficial for the improvement of cognitive function revealed a range of either single herbs or herbal mixtures that provided neuroprotective benefits. Oxidative stress may directly initiate neurodegeneration and herbal antioxidant neuroprotection is considered as a preventative and therapeutic approach. We encountered Acoris gramineus rhizome (AGR), Panax ginseng, Polygala tenuifolia and Poria cocos as the four most frequently used herbs as single/herbal mixtures that were associated with positive cognitive enhancing outcomes. This review focuses on the evidence of their medicinal effects attributed to those constituents present in relatively high concentration.

Evidence for the medicinal and health benefits of polyphenols in green tea for the prevention of chronic diseases such as heart disease, various types of cancer and neurodegenerative diseases is advancing. Their in vivo effectiveness and molecular mechanisms are difficult to elucidate and remain a challenging task. We review the redox responsiveness and amyloid protein perturbation biophysical properties of the major green tea polyphenol constituent (-)- epigallocatechin-3-gallate [EGCG].

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia. Today, only palliative therapies are available. The pathological hallmarks of AD are the presence of neurofibrillary tangles and amyloid plaques, mainly composed of the amyloid-β peptide (Aβ), in the brains of the patients. Several lines of evidence suggest that the increased production and/or decreased cleavage of Aβ and subsequent accumulation of Aβ oligomers and aggregates play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. A wide range of Aβ binding peptides were investigated to date for therapeutic purposes. Only very few were shown to be effective in rodent AD models or in clinical studies. Here, we review those peptides and discuss their possible mechanisms of action.

Protein kinases have emerged as the most important class of targets in oncology drug discovery because of their major roles in regulating cellular growth and survival. At least, 11 kinase inhibitors have received FDA approval to be used as cancer treatments, and there are continuous efforts to bring more candidates from laboratory benches to the clinic. Although many protein kinase inhibitors directly interact with the ATP binding site, other can alter the kinase conformation to prevent productive ATP binding. Herein we discuss the different mechanisms of action of kinase inhibitors and provide classification of the inhibitors according to their binding sites. Some of these are allosteric inhibitors, ATP competitive inhibitors, protein substrate competitive inhibitors, and covalent bond forming inhibitors. This review provides a broad overview of the relation between mechanism of action and the issues of target selectivity and resistance. Special attention was given to the kinase inhibitors currently in clinical trials.

Mango tree, Mangifera indica, has been cultivated in India and several other tropical countries for centuries, and it is a good source of compound ‘mangiferin’. Mangiferin’s xanthonoid structure with C-glucosyl linkage and polyhydroxy component is believed to be crucial for its free radical-scavenging ability leading to a potent antioxidant effect. A number of biological activities of mangiferin have been suggested, including antidiabetic and antiinflammatory abilities. These might be explained by its antioxidant ability as well as its ability to modulate several key inflammatory pathways. Mangiferin has also been shown to be an effective inhibitor of NF-κB signaling pathway. This partially explains its antiinflammatory ability and, additionally, points towards its anticancer potential. The anticancer effects of this compound are just beginning to emerge, and in this comprehensive review, we provide information on what we know about the chemistry and biological effects of mangiferin, which would likely create interest among researchers to design further mechanistic studies in order to better understand and exploit the biological activities of this compound.

This review paper has attempted information specific to the title compound. This survey of the literature data provides useful information about the design and stabilities of the triorganotin with biologically active ligands. Up to now, considerable efforts have been made to synthesize and characterize triorganotin(IV) schiff base complexes with the general formulae R3ML [R = organic group, M: Sn and L: schiff base] and many studies have been focused in order to understand bioassay results. Users with an interest in this substance are strongly encouraged for future research that this is still a very open field.

In this paper, an overview of recent advances of paclitaxel formulations based on nanosystems is provided. Paclitaxel is very effective in the treatment of various cancers especially ovarian and breast cancer, but it demonstrates poor aqueous solubility, which results in the difficulty challenging the development of paclitaxel parenteral formulations, so its clinical application is greatly restricted. The conventional paclitaxel formulation uses Cremophor EL and ethanol to solubilize paclitaxel, which could cause severe side effects. Nanotechnology has been widely exploited in the field of antitumor research, and paclitaxel is no exception. In recent decades, a series of novel formulations of paclitaxel based on nanotechnology have been developed, including albumin-bound paclitaxel, polymeric micelle-formulated paclitaxel, polymer-paclitaxel conjugates, liposome encapsulated paclitaxel etc. The common advantage shared with these novel injectable formulations is that they are developed based on nanotechnology and Cremophor EL-free. In addition, these nanoformulations can significantly reduce toxicities of paclitaxel and greatly promote its antitumor efficiency.