Current Medicinal Chemistry - Volume 17, Issue 22, 2010

Mitochondrial dysfunction acts as a common pathogenetic mechanism in several acute and chronic liver diseases, such as Alcoholic and Non-Alcoholic Fatty Liver Disease (NAFLD), drug-induced steatohepatitis, viral hepatitis, biliary cirrhosis, hepatocellular carcinoma, ischemia/reperfusion injury and transplant rejection. In particular mitochondrial uncoupling has been recently identified to play a determinant role in the pathogenesis of liver diseases by causing decrease of mitochondrial proton motive force and ATP depletion. Damaged mitochondria present defects in lipid homeostasis, bioenergetics impairment and overproduction of Reactive Oxygen Species (ROS), leading to lipid accumulation and oxidative stress. Dysfunctional and/or uncoupled mitochondria enhance the susceptibility of hepatocytes to cell death by necrosis, via ATP depletion, or by apoptosis, via membrane permeabilization. Thus, prevention of mitochondrial alterations promises to be an effective strategy for treatment of liver diseases. However, no therapy has proven to be absolutely effective, whereas those that are beneficial present several side effects. The present review summarizes the recent approaches in mitochondrial drug delivery systems and focuses on mitochondria-targeted molecules application in liver disease. New selective molecules and nanocarriers technology are also considered as potentially effective in the targeting of mitochondrial dysfunction in liver pathology.

γ-Amino butyric acid is an extremely important inhibitory neurotransmitter in the mammalian central nervous system and is essential for the overall balance between neuronal excitation and inhibition. It is well documented that GABA deficiency is associated with several important neurological disorders such as Huntington's chorea, Parkinson's and Alzheimer's disease and other psychiatric disorders, like anxiety, depression, pain, panic, or mania. Although, it is known that increasing the brain concentration of GABA prevents convulsions, the high polarity and flexible structure of this compound are probably responsible for its inefficiency as an anticonvulsant when administered orally or intravenously. To resolve this problem, GABA analogues are being designed. Over recent years, there has been increasing interest in the synthesis and pharmacological effect of new GABA derivatives, which can be considered as potent drugs in the treatment of neurodegenerative disorders.

Traditional medicines have contributed greatly over the centuries to the discovery and development of new therapeutic agents and indoloquinoline alkaloids may represent a new class of drug leads. Cryptolepine (5-methyl-5H-indolo[ 3,2-b]quinoline), neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline), isocryptolepine (5-methyl-5H-indolo[3,2- c]quinoline, extracted from the African medicinal plant Cryptolepis sanguinolenta, and isoneocryptolepine (5-methyl-5H-indolo[ 2,3-c]quinoline), which has never been found in nature, are isomeric tetracyclic compounds of particular interest due to their broad spectrum of biological activities including antiparasitic, antifungal, antibacterial, cytotoxic, antiinflammatory and antihyperglycaemic. As a result, in the last 30 years hundreds of indoloquinoline analogues were synthesized and their biological activities evaluated. In this paper, we present an overview of the potential of indoloquinolines as scaffolds in drug discovery by reviewing the in vitro and in vivo biological activities of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships.

The complex and widespread family of integrin receptors is involved in numerous physiological processes, such as tissue remodeling, angiogenesis, development of the immune response and homeostasis. In addition, their key role has been elucidated in important pathological disorders such as cancer, cardiovascular diseases, osteoporosis, autoimmune and inflammatory diseases and in the pathogenesis of infectious diseases, making them highly important targets for modern drug design campaigns. In this review we seek to present a concise overview of the small molecule antagonists of this diverse and highly complex receptor family. Integrin antagonists are classified according to the targeted integrin receptor and are discussed in four sections. First we present the fibrinogen αIIbβ3 and the vitronectin αVβ3 receptor antagonists. The remaining selective integrin antagonists are examined in the third section. The final section is dedicated to molecules with dual or multiple integrin activity. In addition, the use of antibodies and peptidomimetic approaches to modulate the integrin receptors are discussed, as well providing the reader with an overall appreciation of the field.

Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature in several families of natural products. Among them, the aminoglycoside antibiotics, since the discovery of streptomycin, have become particularly relevant at the forefront of the antibacterial treatment. Another group of aminocyclitols, generally referred to as aminocarbasugars, have been found as key structural components of some families of alkaloids that have evolved as suitable leads for the development of potent glycosidase inhibitors with a vast array of applications in medicinal chemistry, both as therapeutically useful agents as well as valuable pharmacological tools. On the other hand, the aminocyclitol moiety has been used by medicinal chemists as a versatile scaffold in drug design. Thus, in the antiviral arena, it is found as the key component of several families of carbocyclic nucleoside analogues, designed as metabolically stable surrogates of the natural nucleosides. Finally, in a still relatively unexplored area, some aminocyclitol derivatives are being used as key components of artificial receptors for which promising applications in drug research can be envisaged. In all cases, the development of the modern regio- and stereoselective synthetic methodologies enables a large variety of stereochemically defined aminocyclitol analogues in order to study in depth the influence of this moiety on the structure-activity relationships from a given lead.

Lentinus edodes is the first medicinal macrofungus to enter the realm of modern biotechnology. It is the second most popular edible mushroom in the global market which is attributed not only to its nutritional value but also to possible potential for therapeutic applications. Lentinus edodes is used medicinally for diseases involving depressed immune function (including AIDS), cancer, environmental allergies, fungal infection, frequent flu and colds, bronchial inflammation, heart disease, hyperlipidemia (including high blood cholesterol), hypertension, infectious disease, diabetes, hepatitis and regulating urinary inconsistancies. It is the source of several well-studied preparations with proven pharmacological properties, especially the polysaccharide lentinan, eritadenine, shiitake mushroom mycelium, and culture media extracts (LEM, LAP and KS-2). Antibiotic, anti-carcinogenic and antiviral compounds have been isolated intracellularly (fruiting body and mycelia) and extracellularly (culture media). Some of these substances were lentinan, lectins and eritadenine. The aim of this review is to discuss the therapeutic applications of this macrofungus. The potential of this macrofungus is unquestionable in the most important areas of applied biotechnology.

The behavior of fluoride ions in the human organism is a classic example of double-edged sword. On the one hand the daily supplementation with fluoride is undoubtedly an important preventing factor in protecting teeth from caries, and, as an important mitogenic stimulus for osteoblasts, it may enhance mineral deposition in bone, but on the other hand fluoride, above a threshold concentration, has been demonstrated to be toxic. We present here a brief review of fluoride metabolism and exposure, its use in caries prevention and its effects on bone, followed by an updating about the main hypotheses concerning its mechanism of action and toxicity. The effects of fluoride have been related mainly to its ability to evoke the activation of G proteins and the inhibition of phosphotyrosine phosphatases, leading to an intracellular increase of tyrosine phosphorylation and activation of the mitogen-activated protein kinase pathway, and its capacity to cause generation of reactive oxygen species. We present also a unifying hypothesis accounting for these apparently different effects, although the available experimental models and conditions are highly variable in the literature. A lot of experiments still need to be performed to clarify the positive and negative effects of fluoride. Finding the mechanisms accounting for fluoride toxicity is an important point: indeed, the use of fluoride has been proposed in the preparation of new biomaterials to be inserted in the bone, in order to improve their stable and safe integration.