Current Bioactive Compounds - Volume 4, Issue 3, 2008

This special issue of Current Bioactive Compounds is dedicated to anti-aging compounds. The expected life span continues to increase over the World, and we celebrate achievements that made this possible including medical, agricultural, industrial and many others. The dark side of this unquestionable progress is that we have to face a more pronounced affect of aging related diseases on our families and societies. In this issue we concentrated on two common aging related diseases, namely Alzheimer's disease and Parkinson's disease. Three reviews highlight recent achievements in these fields. Due to the major focus of CBC, the authors targeted chemical means that are in progress in these research areas. The opening account by Xudong Huang and his coworkers (Harvard University Medical School and Massachusetts General Hospital, Boston, USA) covers recent developments in the Alzheimer's disease related amyloid-targeted metal chelation, antioxidative stress, and anti-inflammation as potential Alzheimer's therapies. The authors have reviewed the pathogenic roles of brain biometal dysregulation, oxidative stress, and neuroinflammation in AD. The potential Alzheimer's therapies targeting these areas have also been reviewed. The second topic, on the role of iron chelators as potential therapeutic agents for Parkinson's disease has been reviewed by Maolin Guo and his colleagues (University of Massachusetts, Dartmouth, USA). This work summarizes major recent developments in natural and synthetic iron chelating compounds and hydrogen peroxide-triggered prochelators as potential drug candidates for Parkinson's disease treatment. The final contribution to this issue is towards the role of the chemical structure; the effect of substituents of small molecule inhibitors in self-assembly of Alzheimer's disease related amyloid-beta peptide by Marianna Torok and her coworkers (University of Massachusetts, Boston, USA) attempts to analyze the structural characteristics of inhibitors of amyloid beta selfassembly. The work provides an analysis of the most common substituents that are present in Aβ inhibitors and highlights the several chemical moieties that appear significant to their effect. The contributing authors and I truly hope that these accounts will appeal to a wide range of readers who hopefully will find this special issue about anti-aging compounds interesting, informative and useful.

Alzheimer's disease (AD), which accounts for over 80 percent of senile dementia cases, is a polygenic and multifactorial complex disease. However, an overwhelming body of data suggests that the key to AD pathology lies in the biology of a small protein called the Aβ peptide that forms the proteinaceous deposits known as Aβ amyloid that characterizes AD. Considerable progress has been made in understanding the metabolic pathways that generate and clear Aβ. Less well understood are the neurochemical factors that may be important in promoting age-dependent Aβ amyloidosis, the likely precursor to AD. Findings suggest that cerebral biometal dyshomeostasis, oxidative stress, and microglia immune inflammatory responses are intimately involved in Aβ amyloid deposition and AD pathogenesis. With these new findings has come an increasing awareness of the potential of antioxidant/metal chelation/anti-inflammatory therapies as AD treatments. The major impediment to the use of metal chelators and antioxidants are their unfavorable drug profiles that include poor target specificity and low therapeutic potency. However, future development of new bifunctional and multifunctional molecules that contain both amyloid-binding and metal-chelating/antioxidant moieties, is thought to overcome many of the limitations of previous chelating and antioxidant drugs. Herein we have reviewed the pathogenic roles of brain biometal dysregulation, oxidative stress, and neuroinflammation in AD. We have also discussed the potentials of amyloid-targeted metal chelation, anti-oxidative stress, and anti-inflammation as potential Alzheimer's therapies.

Parkinson's disease (PD) is a neurological disorder characterized by the progressive impairment of motor skills in patients. Growing evidence suggests that abnormal redox-active metal accumulation, caused by dysregulation, plays a central role in the neuropathology of PD. Redox-active metals (e.g. Fe and Cu) catalyze essential reactions for brain function. However, these metals can also participate in the generation of highly toxic free radicals that can cause oxidative damage to cells and ultimately lead to the death of dopamine-containing neurons. The emergence of redox-active metals as key players in the pathogenesis of PD strongly suggests that metal-chelators could be beneficial in the treatment of this condition. This mini-review summarizes major recent developments on natural, synthetic iron chelating compounds and hydrogen peroxide-triggered prochelators as potential candidates for PD treatment.

The role of the chemical structure, namely the effect of substituents, of small molecule inhibitors in selfassembly of Alzheimer's disease related amyloid-beta peptide is discussed. The literature analysis is concentrated on the past 10 years and analyzed the structure of Aβ inhibitors pointing out common features. A basis set of 321 compounds is reviewed and a chemical map of the inhibitors is provided highlighting the most common substituents that appear in these molecules. Based on the findings, aromatic/heteroaromatic groups were found to be present in an overwhelming majority of inhibitors (95%). Acidic substituents appeared the second most common substituent group (67%) suggesting the importance of these motifs as possible binding units. Several structure activity relationship studies that support this role are also discussed.

The interactions of synthetic and natural anthracyclines were studied by determination of binding constants to calf thymus DNA using spectrophotometric titration and thermal denaturation of drug-DNA solutions to determine the Tm values. The two ways of evaluation of DNA-drug interaction showed reasonable correlation. In particular, the glycosides with non-natural aglycones or major structural deviation showed consistently lower binding constants and Tm values. In the case of daunorubicin and 4-demethoxydaunorubicin these data also correlated reasonably with antitumor efficacy. However, in other instances, there were many deviations and a direct simple correlation between binding parameters and biological activity can not be established.

The plant kingdom is a rich source of compounds with anticancer activities. Curcumin [1,7-bis(4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione] (1) is a secondary metabolite produced by rhizomes of Curcuma longa that has been used for centuries in traditional Medicine in Asia. Anticancer activity is one of the pharmacological properties of curcumin (1) that has been widely explored. Its targets include transcription factors, growth and angiogenesis regulators, apoptosis-related genes, adhesion-related molecules, and cellular signaling molecules. Some curcumin conjugates and metallocomplexes have been synthesized, characterized and evaluated for anticancer activity. In this mini-review, we discuss the mechanism of action by which curcumin (1) inhibits the progression of tumor growth and also the antiproliferative activity of curcumin conjugates and metallocomplexes on human cancer cells. The understanding of how these conjugates and metallocomplexes exert their anticancer activities is essential for future development of effective drugs.