Current Medicinal Chemistry (v.22, #33)

Meet Our Editorial Board Member: by Nikos Tagmatarchis (3763-3764).

Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases by D. Lauro, D. Pastore, B. Capuani, F. Pacifici, R. Palmirotta, P. Abete, M. Roselli, A. Bellia, M. Federici, N. Di Daniele, P. Sbraccia, F. Guadagni, R. Lauro, D. Della-Morte (3765-3788).
Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na+/K+ regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

From Bitopic Inhibitors to Multitarget Drugs for the Future Treatment of Alzheimer's Disease by Daniel I. Perez, Ana Martinez, Carmen Gil, Nuria E. Campillo (3789-3806).
Dementia is one of the main causes of the disease burden in developed regions. According to the World Health Organization (WHO), it will become the world's second leading cause of death by the middle of the century, overtaking cancer. This will have a dramatic impact on medical care, and have important social and economic implications, unless more effective preventive procedures or treatments become available. Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 50-75% of all dementias worldwide, followed by vascular dementia, mixed dementia, and Lewy body dementia.
Currently, acetylcholinesterase (AChE) inhibitors, such as donepezil, rivastigmine and galantamine are used to treat mild to moderate AD. An alternative therapy for severe AD is memantine, an antagonist of the NMDA-subtype of glutamate receptors. However, these drugs provide only temporary symptom improvement, and do not alter disease progression, except temporarily in some patients.
In recent years different approaches have been developed to provide a more effective treatment for AD. These approached include the discovery of emerging targets and new drugs aiming at a single target, but given the complexity of the disease, different targets may need to be engaged simultaneously. New strategies have explored bitopic inhibitors, for example a single drug that acts on different sites of the acetylcholinesterase enzyme to produce at least two different activities, and multitarget drugs that act on multiple therapeutic targets.
In this review, we explore the journey from a bitopic inhibitor strategy to multitarget drugs for the future treatment of AD.

5-Aminoisoquinolin-1-one (5-AIQ) is a water-soluble inhibitor of the poly(ADPribose) polymerases (PARPs), lacking isoform-selectivity. Although of only moderate potency in vitro against PARP-1, it is highly active in many assays in cells and in models in vivo, indicating excellent uptake. Optimisation of the several synthetic sequences to 5-AIQ has led to development of a short and efficient route from 1-chloroisoquinoline. It has been used widely as a biochemical and pharmacological tool to study the effects of inhibition of the PARPs. It ameliorates the damage to cells and tissues following reperfusion of ischaemic tissue, showing significant protective activity in a rodent model of haemorrhagic shock at the remarkably low dose of 30 µg Kg-1. Protection is also seen in models of myocardial infarction, ischaemic kidney and liver disorders, stroke and organ transplantation. Inhibition of PARP-1 by 5-AIQ causes down-regulation of the activity of NF-κB, which then down-regulates the expression of several gene products. Thus 5-AIQ has anti-inflammatory activity in vivo, through modulating the expression of cytokines and adhesion molecules. This indirect inhibition of expression is relevant in the activity of 5-AIQ in models of arthritis, Parkinson's disease, multiple sclerosis, spinal cord injury, periodontitis and inflammatory conditions of the lung. Inhibition of expression of matrix metalloproteinases and other factors gives rise to anti-angiogenic activity and to remarkable anti-metastatic activity in a mouse model. Thus, although it has been overtaken by other PARP-inhibiting drugs in the oncological clinic, 5-AIQ remains a valuable tool to study the roles of PARPs in health and in diverse diseases.

Inhibitors of Angiogenesis in Cancer Therapy - Synthesis and Biological Activity by Monika Gensicka, Agnieszka Glowacka, Krystyna Dzierzbicka, Grzegorz Cholewinski (3830-3847).
Angiogenesis is the process of formation of new capillaries from preexisting blood vessels. Angiogenesis is involved in normal physiological processes, and plays an important role in tumor invasion and development of metastases. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. VEGF is a mitogen for vascular endothelial cells and stimulates their proliferation. By inhibiting the biological activity of VEGF, and then signal cascades with neutralizing VEGF antibodies and signal inhibitors, may negatively regulate the growth and metastasis. Anti-angiogenesis therapy is less toxic than chemotherapy. Angiogenesis is a multistep and multifactorial process, and therefore, can be blocked at different levels. In this review article, the authors present the synthesis of novel inhibitors of angiogenesis, together with the results of biological tests in vitro, and in some cases, state trials.

Potential Relevance of Melatonin Against Some Infectious Agents: A Review and Assessment of Recent Research by Ehab Kotb Elmahallawy, Javier Ortega Luque, Abdelkarim Saleh Aloweidi, Jose Gutierrez -Fernandez, Antonio Sampedro-Martinez, Javier Rodriguez-Granger, Abdullah Kaki, Ahmad Agil (3848-3861).
Melatonin, a tryptophan-derived neurohormone found in animals, plants, and microbes, participates in various biological and physiological functions. Among other properties, numerous in vitro or in vivo studies have reported its therapeutic potential against many parasites, bacteria and viruses. In this concern, melatonin was found to be effective against many parasites such as Plasmodium, Toxoplasma gondii, and Trypansoma cruzi, via various mechanisms such as modulation of calcium level and/or host immune system. Likewise, a recent investigation has reported in vitro activity of melatonin against Leishmania infantum promastigotes which is the causative agent of fascinating visceral Leishmaniasis. This review was initially undertaken to summarize some facts about certain physiological and therapeutic effects of melatonin. It also reviews the effects and action mechanisms of melatonin in bacterial and viral infection besides biology of different parasites which may provide a promising strategy for control of many diseases of public health importance.