Mini-Reviews in Organic Chemistry - Volume 7, Issue 4, 2010

Currently, cardiovascular diseases and cancer are the leading causes of death and illness worldwide. Research dealing with the identification of naturally occurring substances that serve as therapeutic agents has led to in-depth studies on resveratrol (3,4',5- trihydroxystilbene) which has been shown to have diverse pharmacological properties, including in cancer chemoprevention and in the protection against cardiovascular and neurodegenerative diseases. In this special issue, the molecular mechanism of resveratrol's beneficial effects on various diseases has been summarized by different experts in the field. An interest in this polyphenol compound initially arose due to a phenomenon called the “French Paradox”, which refers to a low incidence of cardiovascular diseases among the French population despite a high fat diet. Thus this issue started with the first review by Dr. Das and his colleagues, which particularly summarizes the mechanisms of cardio-protection, the progress in the chemical and biological production of resveratrol and its derivatives, their biological targets and bioavailability. The second review by Dr. Fulda presents how resveratrol regulates cell survival and cell death signalling, which is expected to open new avenues for the exploitation of resveratrol in the prevention and treatment of cancer. Finally, a review by Dr. Pallas et al. summarizes how resveratrol affects cell cycle and mediates life-span increase, and particularly how resveratrol performs its neuroprotection activity. We can conclude and imagine from these reviews that resveratrol shows diverse effects on a wide range of diseases, which makes it an attractive compound for therapeutic purposes. This might provoke the following response from our readers; “Sounds interesting, we need more production!” To this end, the last review in this issue, deals with the methods of production of resveratrol including extraction, chemical synthesis and biotechnology. Additionally, the stability, bioavailability, as well as the structure-activity relationships of resveratrol and its analogues have also been discussed to stimulate further development of more stable and effective analogues. In summary, I hope this special issue will provide a good impact on readers with an overview of resveratrol and future strategies for its potential pharmacological uses. Finally, as a guest editor for this special issue, I am very grateful for the valuable and excellent contributions from my colleagues and I am also highly appreciative of all the referees for their expert comments on the papers, despite their tight schedules and for their precious time. My sincere thanks to Miss Qurrat-ul-Ain Khan for her nice cooperation as well as to the editors of MROC for giving me the chance to organize this special issue on this exciting topic. I hope that the readers will enjoy reading the complete issue.

In recent years, resveratrol has become a popular nutritional supplements used by humans all over the world. Much research has been conducted to determine the efficacy of its use both in preventive and therapeutic dimensions. Usage of functional foods with a history of ethno-use with no known side effects is an area of great interest in improving the overall health condition of the population. Resveratrol, with its known potency and wide variety of health benefits has shown promising results in minimizing cardiovascular complications including hypertension, hypertrophy, ischemic heart disease and atherosclerosis. However, a great deal of controversy exists regarding the use of resveratrol as an anti-aging compound. In this review, progress in the chemical and biological production of resveratrol and its derivatives, their biological targets, bioavailability as well as the mechanisms of resveratrol cardio-protection will be discussed.

Tissue homeostasis is maintained by tight control of signaling events that regulate cell death and cell survival. Apoptosis or programmed cell death plays a key role in maintaining tissue homeostasis under various conditions during normal development and in the adult organism. Thus, defective apoptosis programs contribute to the pathogenesis of various human diseases, for example to cancer formation. In addition, the antitumor activity of most cancer therapies, including chemotherapy, radiotherapy or immunotherapy, is mediated by the activation of apoptosis in cancer cells. Natural compounds including resveratrol have attracted much attention over the last decade both as cancer chemopreventive agents and as cancer therapeutics. To this end, resveratrol inhibits signal transduction pathways that block apoptosis and/or promote cell survival. Insights into the molecular mechanisms of how resveratrol regulates cell survival and cell death signaling is expected to open new avenues for the exploitation of resveratrol in the prevention and treatment of cancer.

Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenol present in black grapes and its derivatives. Several reports have shown that resveratrol can prevent or slow the progression of a wide variety of illnesses, including cancer, cardiovascular disease and ischemic injuries as well as enhances stress resistance and extends the lifespan of various organisms from yeast to mammals. The mechanism by which resveratrol exerts such a range of beneficial effects across species and disease models is not yet clear, although at the beginning it was proposed that the antioxidant properties of this drug may explain the majority of its beneficial effects. Another mechanism by which resveratrol could combat tumour formation is induction of cell cycle arrest and apoptosis. The last protective mechanism related with resveratrol is its role as activator of sirtuin 1. Resveratrol increases the affinity of sirtuin 1 for its acetylated substrates, possibly inducing a conformational change of the enzyme. The axis sirtuin 1/PGC-1 activated by the resveratrol is a signalling pathway involved in several cellular contexts and tissues, each of the actors involved may promote a separate slow down in the neurodegenerative process. This neuroprotective action is very likely due the fact that the central factor of this signal, PGC-1, promotes mitochondrial activity while neurodegenerative diseases are linked to mitochondrial failures. It is strongly suggested that the activation of the axis sirtuin 1 /PGC-1 by resveratrol could be a key feature of the mechanisms of neuroprotection by this polyphenol and give birth to new therapeutic prospects.

Given the pharmacological importance of resveratrol, preparation methods, including plant extraction, chemical synthesis and biotechnological production are evolving rapidly aiming at a large scale production. Plant extraction is the classical method providing major amount of this compound, however, it suffers from low abundance of resveratrol in natural material and environmental, seasonal, or regional variations of natural sources. Complexity of synthetic pathway and the low total yield constrain the industrial application of chemical synthesis. In contrast, biotechnological means offer significantly promising and scalable strategies for resveratrol production while using low-cost and renewable resources. In the present paper, both advantages and disadvantages of these preparation methods as well as the bioavailability and structure-activity relationship of resveratrol have been summarized and discussed aiming to provide valuable information for future improvement of resveratrol production and for searching of a stable and effective resveratrol analogue for therapeutic purposes.

There is currently a threat posed by the rapid emergence of antibiotic-resistant pathogens due to the abuse of conventional antibiotics. To overcome such a resistance problem, it is necessary to develop peptide agents with potent antimicrobial activities and high selectivity for target bacterial strains. Conventional approaches, such as the deletion, addition, and replacement of amino acid residues in the template peptide have been employed to alter the properties of antimicrobial peptides (AMPs). In this review, we summarize a recently developed approach, chemical modification, for the improvement of various types of naturally-occurring AMPs. By applying this design strategy to these peptide sequences, new AMPs with enhanced antimicrobial activities and improved selectivity for microorganisms have been successfully generated. This potential strategy should facilitate the creation of novel class of peptide antibiotics with properties suitable for pharmaceutical application.

Glycosaminoglycans (GAGs) occur in many tissues. There is increasing evidence that the sulfation of GAGs does not occur at random, but a “sulfation code” exists that mediates the physiological functions of GAGs. Therefore, certain GAGs might also have interesting pharmacological properties. We will give here an overview on chemical functionalization strategies of hyaluronan (HA) and chondroitin/ dermatan sulfate (CS/DS). This is a challenging task from the synthetic as well as analytical viewpoint because both, regioselective GAG modifications with defined molecular weights and methods to unequivocally characterize the structures of the modified GAGs must be adapted and/or developed. Consequently, in the last part of this review, methods of GAG characterization will be introduced and their capabilities and limitations discussed.

Hopanoids, widespread compounds of triterpene nature, are found mainly in different bacterial types (G+ and G- bacteria, aerobs, facultative anaerobs, strict anaerobs), in methanotrophs, acetic acid bacteria, nitrogen fixers, purple non-sulphur bacteria, cyanobacteria, and also in sediments. They occur in a variety of structures from simple hopanoids to elongated compounds with polyfunctional side chains such as bacteriohopanepolyols (BH-polyols). This review summarizes current knowledge of the occurrence of these compounds in different bacterial types, genera and species, their biosynthesis and functions in cellular membranes and in important biochemical and physiological processes, and surveys advances and trends in the field of hopanoid analysis, especially as concerns LC-MS with soft ionization techniques such as APCI and/or ESI.

This review attempts to sum up all the synthetic accesses to 3/5-pyrazole carboxylic acids or esters published, or patented, in the last 120 years. Many of them have demonstrated their robustness as well as quite large scopes. However, a majority are relying on the regioselectivity of reactions such as ketones deprotonations, cyclocondensations or [2+3] cycloadditions. For this reason, the preparation of original 3/5-carboxypyrazoles featuring a structure departing from the inherent regioselectivity of these synthetic accesses could be problematic. Moreover, a large scale synthesis of some 3/5-carboxypyrazoles could be a real challenge. It is thus reasonable to forecast that even more synthetic methodologies should be reported in the future in attempts to meet such requirements.

N-heterocyclic germylenes NHGe have recently come of age. In the last few years, they emerged as mature ligands capable of functionalisation, chirality, electronic tuning and chelating bis-NHGe ligands. The review shows the major trends and developments of the last five years.

Berberine, a fluorescent, aromatic, heterocyclic alkaloid, produced in a diversity of plants, was found to have curative properties in Chinese herbal medicine. Berberine is used as a treatment for gastric and inflammatory diseases and as an antimicrobial agent. More recently the potential of this alkaloid in diverse new medical application like cardiology, neurology and oncology is being investigated. As a result of its fluorescent properties, it has also been used in chemistry to study protein conformation and protein/protein interactions and to quantitate non-fluorescent compounds. All these applications will be summarized and discussed in this review.