Showing papers in "Current Medicinal Chemistry in 2011"
TL;DR: In vitro and in vivo anticancer activities of quinoline and its analogs are focused on in the context of cancer drug development and refinement, and selective and specific activity against various cancer drug targets are reviewed.
Abstract: Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that contains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as "parental" compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based compounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activities, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.
468 citations
TL;DR: Recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed and some suggestions are provided to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.
Abstract: Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.
367 citations
TL;DR: This review provides a comprehensive and unprecedented literature compilation concerning the synthesis and biological evaluation of various cinnamoyl acids, esters, amides, hydrazides and related derivatives in anticancer research.
Abstract: Cinnamic acid and its phenolic analogues are natural substances. Chemically, in cinnamic acids the 3-phenyl acrylic acid functionality offers three main reactive sites; substitution at the phenyl ring, addition at the α,β-unsaturation and the reactions of the carboxylic acid functionality. Owing to these chemical aspects cinnamic acid derivatives received much attention in medicinal research as traditional as well as recent synthetic antitumor agents. We observed that in spite of their rich medicinal tradition, cinnamic acid derivatives and their anticancer potentials remained underutilized for several decades since the first published clinical use in 1905. In last two decades, there has been huge attention towards various cinnamoyl derivatives and their antitumor efficacy. This review provides a comprehensive and unprecedented literature compilation concerning the synthesis and biological evaluation of various cinnamoyl acids, esters, amides, hydrazides and related derivatives in anticancer research. We envisage that our effort in this review contributes a much needed and timely addition to the literature of medicinal research.
333 citations
TL;DR: This review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties, and updates and expands the 2006 review by the same author.
Abstract: Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.
303 citations
TL;DR: Aptamers are in several stages of development, from pre-clinical studies to clinical trials and even as FDA approved therapeutics, as well as some promising aptamers in pre- clinical development.
Abstract: Aptamers are a special class of nucleic acid molecules that are beginning to be investigated for clinical use. These small RNA/DNA molecules can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets; they are essentially a chemical equivalent of antibodies. Aptamers have the advantage of being highly specific, relatively small in size, and non-immunogenic. Since the discovery of aptamers in the early 1990s, great efforts have been made to make them clinically relevant for diseases like cancer, HIV, and macular degeneration. In the last two decades, many aptamers have been clinically developed as inhibitors for targets such as vascular endothelial growth factor (VEGF) and thrombin. The first aptamer based therapeutic was FDA approved in 2004 for the treatment of age-related macular degeneration and several other aptamers are currently being evaluated in clinical trials. With advances in targeted-therapy, imaging, and nanotechnology, aptamers are readily considered as potential targeting ligands because of their chemical synthesis and ease of modification for conjugation. Preclinical studies using aptamer-siRNA chimeras and aptamer targeted nanoparticle therapeutics have been very successful in mouse models of cancer and HIV. In summary aptamers are in several stages of development, from pre-clinical studies to clinical trials and even as FDA approved therapeutics. In this review, we will discuss the current state of aptamers in clinical trials as well as some promising aptamers in pre-clinical development.
296 citations
TL;DR: The different features observed in PDT resistance are classified, leading to a comparison with the mechanisms most commonly found in chemo resistant cells.
Abstract: Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by illumination with visible light, leading to generation of reactive oxygen species. The mechanisms of resistance to PDT ascribed to the PS may be shared with the general mechanisms of drug resistance, and are related to altered drug uptake and efflux rates or altered intracellular trafficking. As a second step, an increased inactivation of oxygen reactive species is also associated to PDT resistance via antioxidant detoxifying enzymes and activation of heat shock proteins. Induction of stress response genes also occurs after PDT, resulting in modulation of proliferation, cell detachment and inducing survival pathways among other multiple extracellular signalling events. In addition, an increased repair of induced damage to proteins, membranes and occasionally to DNA may happen. PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption may also contribute to the appearance of resistant cells. The structure of the PS is believed to be a key point in the development of resistance, being probably related to its particular subcellular localization. Although most of the features have already been described for chemoresistance, in many cases, no cross-resistance between PDT and chemotherapy has been reported. These findings are in line with the enhancement of PDT efficacy by combination with chemotherapy. The study of cross resistance in cells with developed resistance against a particular PS challenged against other PS is also highly complex and comprises different mechanisms. In this review we will classify the different features observed in PDT resistance, leading to a comparison with the mechanisms most commonly found in chemo resistant cells.
250 citations
TL;DR: This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets.
Abstract: Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs). This methodology has been specifically developed for treatment of disorders with complex pathological mechanisms. One such disorder is Alzheimer's disease (AD), currently the most common multifactorial neurodegenerative disease. AD is related to increased levels of the amyloid β peptide (Aβ) and the hyperphosphorylated tau protein, along with loss of neurons and synapses. Moreover, there is some evidence pointing to the role of oxidative stress, metal ion deregulation, inflammation and cell cycle regulatory failure in its pathogenesis. There are many attractive targets for the development of anti-AD drugs, and the multi-factor nature of this disease calls for multi-target-directed compounds which can be beneficial for AD treatment. This review presents the discovery of dualand multi-acting anti-AD drug candidates, focusing on the novel design strategy and the compounds it yields - particularly hybrids obtained by linking structurally active moieties interacting with different targets. The first group of compounds includes cholinesterase inhibitors acting as dual binding site inhibitors and/or inhibitors with additional properties. These compounds are characterized by increased potency against acetylcholinesterase (AChE) and Aβ plaque formation with additional properties such as antioxidant activity, neuroprotective, and metal-complexing property, voltage-dependent calcium channel antagonistic activity, inhibitory activity against glutamate-induced excitotoxicity, histamine H3 receptor antagonism, cannabinoid CB1 receptor antagonism and β-secretase (BACE1) inhibition. A novel class of compounds represents the combination of dual BACE1 inhibitors with metal chelators, and dual modulators of γ-secretase with peroxisome proliferator-ativated receptor γ (PPARγ). We have reviewed the latest reports (2008-2011) presenting new multi-target-directed compounds in Alzheimer's disease treatment.
210 citations
TL;DR: This review will highlight the most important findings obtained testing AMPs in in vitro and in vivo models of bacterial biofilms, pointing out the possible advantages and limits of their use against microbial biofilm-related infections.
Abstract: The formation of surface-attached cellular agglomerates, the so-called biofilms, contributes significantly to bacterial resistance to antibiotics and innate host defenses. Bacterial biofilms are associated to various pathological conditions in humans such as cystic fibrosis, colonization of indwelling medical devices and dental plaque formation involved in caries and periodontitis. Over the last years, natural antimicrobial peptides (AMPs) have attracted considerable interest as a new class of antimicrobial drugs for a number of reasons. Among these, there are the broad activity spectrum, the relative selectivity towards their targets (microbial membranes), the rapid mechanism of action and, above all, the low frequency in selecting resistant strains. Since biofilm resistance to antibiotics is mainly due to the slow growth rate and low metabolic activity of bacteria in such community, the use of AMPs to inhibit biofilm formation could be potentially an attractive therapeutic approach. In fact, due to the prevalent mechanism of action of AMPs, which relies on their ability to permeabilize and/or to form pores within the cytoplasmic membranes, they have a high potential to act also on slow growing or even non-growing bacteria. This review will highlight the most important findings obtained testing AMPs in in vitro and in vivo models of bacterial biofilms, pointing out the possible advantages and limits of their use against microbial biofilm-related infections.
189 citations
TL;DR: It will be shown that hybrids can be more than the sum of their components, but in many cases should be considered as pharmacological entities in their own respect.
Abstract: In this article the design of hybrid molecules that covalently connect two distinct drug entities in one molecule, at least one part being a biologically active natural product will be discussed. In the quest for novel drug entities, the hybrid approach is a promising path to drug molecules that can effectively target multifactorial diseases including neurodegenerative disorders like Alzheimer's and Parkinson's diseases (AD and PD). The hybrid approach can also be used to optimize certain biological properties like affinity and selectivity, but also to gain novel biological activities distinct from the ones of the components. Due to the high potential of natural products to exhibit pronounced biological activities, natural products have been one of the major sources of components in hybrid molecules. This review will cover their applications in developing drugs for neurodegenerative disorders, in the diverse field of anti-cancer agents (which represents the major application for natural products in medicinal chemistry), but also in miscellaneous areas of bioactive compounds including antioxidants, antimalarial drugs and estrogen-related hybrids to reach various therapeutic aims. The unique tasks of hybrid molecule design will be addressed, such as describing suitable ways to chemically connect the drug components, how to use the approach to enhance biological activity with respect to both activity and selectivity and potential drawbacks of the hybrid approach. It will be shown that hybrids can be more than the sum of their components, but in many cases should be considered as pharmacological entities in their own respect.
177 citations
TL;DR: The focus of this review is on the development of aptamer-based fluorescent biosensors, with emphasis on their design as well as properties such as sensitivity and specificity.
Abstract: Selected from random pools of DNA or RNA molecules through systematic evolution of ligands by exponential enrichment (SELEX), aptamers can bind to target molecules with high affinity and specificity, which makes them ideal recognition elements in the development of biosensors. To date, aptamer-based biosensors have used a wide variety of detection techniques, which are briefly summarized in this article. The focus of this review is on the development of aptamer-based fluorescent biosensors, with emphasis on their design as well as properties such as sensitivity and specificity. These biosensors can be broadly divided into two categories: those using fluorescently-labeled aptamers and others that employ label-free aptamers. Within each category, they can be further divided into "signal-on" and "signal-off" sensors. A number of these aptamer-based fluorescent biosensors have shown promising results in biological samples such as urine and serum, suggesting their potential applications in biomedical research and disease diagnostics.
176 citations
TL;DR: Some representative studies related to the use of fullerenes for drug-like functions and for their improving the formulation of established drugs are highlighted, including their serving as potent agents in photodynamic therapy and magnetic imaging.
Abstract: Fullerenes as a unique class of carbon allotropes have been studied extensively for their distinctive material properties and potential technological applications, including those in biology and medicine. Since a major focus in the latter has been on drug development and formulation, in this paper we highlight some representative studies related to such a focus, including the use of fullerenes for drug-like functions and for their improving the formulation of established drugs. Also discussed are some other potential medically relevant applications of fullerenes, such as their serving as potent agents in photodynamic therapy and magnetic imaging.
TL;DR: In this opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community.
Abstract: Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue.
TL;DR: Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer, and selective estrogen-receptor modulators, such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice.
Abstract: Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.
TL;DR: A survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants is given, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.
Abstract: With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Δ(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology.
TL;DR: In various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance.
Abstract: Cancers are the largest cause of mortality and morbidity in industrialized countries In the field of the medicinal chemistry of natural products, numerous studies have reported interesting properties of trans-resveratrol as a chemopreventing agent against cancers, inflammation, and viral infection Tumor growth inhibition has been linked to the ability of resveratrol to arrest cell cycle progression and to trigger cell death This review focuses on the pathways that mediate resveratrol-induced cell death Resveratrol impacts on the mitochondrial functions (respiratory chain, oncoproteins, gene expression, etc), in which p53 protein can be involved and its acetylated or phosphorylated forms This polyphenol also affects death receptor distribution in ceramide-enriched membrane platforms which serve to trap and cluster receptor molecules, and facilitates the formation of a death-inducing signaling complex in the cell To induce apoptosis, resveratrol also activates the ceramide / sphingomyelin pathway, which promotes ceramide generation and the downstream activation of kinase cascades Resveratrol can activate alternative pathways to cell death such as those leading to autophagy, senescence or mitotic catastrophe Furthermore, numerous attempts have been made using resveratrol analogs to improve the molecule's ability to block cell proliferation and induce cell death Moreover, structural modification of natural phenolics is expected to produce analogs that may be useful tools to study the structure-activity relationships Lastly, in various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance
TL;DR: The aim of the present article is to review the pathophysiological mechanisms that have been proposed for the observed association between LLC and cardiovascular diseases (CVD), the available evidence regarding the diagnostic and prognostic role attributable to LLC in patients with CVD, and the potential therapeutic implications of these findings.
Abstract: Inflammation plays a crucial pathophysiological role in the entire continuum of the atherosclerotic process, from its initiation, progression, and plaque destabilization leading ultimately to an acute coronary event. Furthermore, once the clinical event has occurred, inflammation also influences the left ventricular remodelling process. Under the same paradigm, there is evidence that lymphocytes play an important role in the modulation of the inflammatory response at every level of the atherosclerotic process. Low lymphocyte count (LLC) is a common finding during the systemic inflammatory response, and clinical and animal studies suggest that LCC plays a putative role in accelerated atherosclerosis. For instance, there is recent evidence that LLC is associated with worse outcomes in patients with heart failure, chronic ischemic heart disease and acute coronary syndromes. Further indirect evidence supports the pathologic role of LLC related to the fact that 1) lymphopenia--due to a decreased count of lymphocyte T cells--normally occurs as a part of the human ageing process, and 2) increased incidence of cardiovascular events has been reported in conditions where lymphopenia is common, such as renal transplant recipients, human immunodeficiency virus infection, survivors of nuclear disasters and autoimmune diseases. The aim of the present article is to review: a) the pathophysiological mechanisms that have been proposed for the observed association between LLC and cardiovascular diseases (CVD), b) the available evidence regarding the diagnostic and prognostic role attributable to LLC in patients with CVD, and; c) the potential therapeutic implications of these findings.
TL;DR: The review intends to conduct a systematic analysis of the literature in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians.
Abstract: Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plantderived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines. Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD. In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.
TL;DR: Evidence suggests that the bioavailability of anthocyanins varies markedly depending on food matrices, including other antioxidants and macronutrients present in foods consumed, which consequently affects the absorption and antioxidant capacity of anthcyanins.
Abstract: Anthocyanins, abundant in deep-colored fruits and vegetables, have received considerable attention due to their potential health benefits. However, the bioavailability of anthocyanins is relatively low compared to that of other flavonoids. While previous reviews focused on the absorption, metabolism and excretion of anthocyanins, little information is available on the effects of food matrix on anthocyanin bioavailability, particularly food matrices of the usual diet. The present review includes the recent studies on interactive effects of anthocyanins and certain food components. Evidence suggests that the bioavailability of anthocyanins varies markedly depending on food matrices, including other antioxidants and macronutrients present in foods consumed, which consequently affects the absorption and antioxidant capacity of anthocyanins. Further studies are needed to gain insight into the mechanisms underlying the interactive effects of anthocyanins and food components in their bioavailability and antioxidant capacity of anthocyanins at the physiological level.
TL;DR: This review will focus on the most significant achievements in the discovery of antifungal lead structures within last few years and pay more attention on the structure-activity relationship of antIFungal leads and provide perspectives for future antifundal drug discovery.
Abstract: During the past two decades, the incidence of invasive fungal infections has been increasing dramatically. Clinical available antifungal agents have several drawbacks such as limited potency and spectrum, drug related toxicity, non-optimal pharmacokinetics, and severe resistance. There is an emergent need to develop new antifungal drugs with novel chemical structures and novel mechanism of action. This review will focus on the most significant achievements in the discovery of antifungal lead structures within last few years. In particular, we pay more attention on the structure-activity relationship of antifungal leads and provide perspectives for future antifungal drug discovery.
TL;DR: In this review, chemical modifications to increase the stability of three main types of aptamers, DNA, RNA and peptide are comprehensively summarized.
Abstract: Ever since the invention of SELEX (systematic evolution of ligands by exponential enrichment), there has been rapid development for aptamers over the last two decades, making them a promising approach in therapeutic applications as either drug candidates or diagnostic tools. For therapeutic purposes, a durable performance of aptamers in biofluids is required, which is, however, hampered by the lack of stability of most aptamers. Not only are the nucleic acid aptamers susceptible to nucleases, the peptide aptamers are also subjective to degradation by proteases. With the advancement of chemical biology, numerous attempts have been made to overcome this obstacle, many resulting in significant improvements in stability. In this review, chemical modifications to increase the stability of three main types of aptamers, DNA, RNA and peptide are comprehensively summarized. For nucleic acid aptamers, development of modified SELEX coupled with mutated polymerase is discussed, which is adaptive to a number of modifications in aptamers and in a large extent facilitates the research of aptamer-modifications. For peptide aptamers, approaches in molecular biology with introduction of stabilizing protein as well as the switch of scaffold protein are included, which may represent a future direction of chemical conjugations to aptamers.
TL;DR: This work focuses on natural and synthetic flavonoids inhibitors of the enzyme acetylcholinesterase (AChE), which are classified in chemical structure and summarizes 64 references.
Abstract: Flavonoids are new promising potential natural compounds for treating Alzheimer's disease (AD). Actually most promising drugs for symptomatic treatment of AD are acetylcholinesterase inhibitors (AChEI). Flavonoids with AChE inhibitory activity and due to their well known antioxidant activity could be new multipotent drugs for AD treatment. This work focuses on natural and synthetic flavonoids inhibitors of the enzyme acetylcholinesterase (AChE). Over, all this review refers to 128 flavonoids, which are classified in chemical structure, and summarizes 64 references.
TL;DR: The current knowledge of the mechanisms regulating tight junctions and intestinal permeability are described, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.
Abstract: The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are.
TL;DR: Accumulating evidence demonstrates that PDK1 is a valid therapeutic target and suggests thatPDK1 inhibitors may be useful to prevent cancer progression and abnormal tissue dissemination.
Abstract: Abnormal activation of phosphoinositide 3-kinase (PI3K) signalling is very common in cancer, leading to deregulation of several intracellular processes normally controlled by this enzyme, including cell survival, growth, proliferation and migration. Mutations in the gene encoding the tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which leads to uncontrolled activation of the PI3K pathway, are reported in different cancers. Among the downstream effectors of PI3Ks, 3- phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB)/Akt have a key role in several cancer types. More recent data indicate that alteration of PDK1 is a critical component of oncogenic PI3K signalling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. PDK1 has an essential role in regulating cell migration especially in the context of PTEN deficiency. Downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells. PDK1 activates a large number of proteins, including Akt, some PKC isoforms, S6K and SGK. Data also reveal that PDK1 is oncogenic and this is dependent on PI3K pathway. Therefore, accumulating evidence demonstrates that PDK1 is a valid therapeutic target and suggests that PDK1 inhibitors may be useful to prevent cancer progression and abnormal tissue dissemination. This review will focus on published data on the role of PDK1 in cancer and approaches used to inhibit PDK1.
TL;DR: Evidence is provided that polyphenols can effectively modulate intestinal inflammation by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector.
Abstract: Inflammatory bowel disease (IBD) comprises a group of idiopathic chronic intestinal inflammation syndromes that are very common in developed countries. It is characterized by intermittent episodes of clinical remission and relapse, with recurrent inflammatory injury that can lead to structural damage of the intestine. The uncontrolled intestinal immune response to bacterial antigens leads to the production of abundant cytokines and chemokines, by activated leukocytes and epithelial cells, which trigger inflammatory and oxidative reactions. The current treatment of IBD consists in long-term anti-inflammatory therapy that, however, does not exclude relapses and side effects, frequently resulting in surgical intervention. Polyphenols have been acknowledged to be anti-oxidant and anti-inflammatory and therefore, have been proposed as an alternative natural approach to prevent or treat chronic inflammatory diseases. Most studies have been in animal models of colitis, using chemical inducers or mice defective in anti-inflammatory mediators and in intestinal cell lines treated with pro-inflammatory cytokines or lipid oxidation products. These studies provide evidence that polyphenols can effectively modulate intestinal inflammation. They exert their effects by modulating cell signaling pathways, mainly activated in response to oxidative and inflammatory stimuli, and NF-kB is the principal downstream effector. Polyphenols may thus be considered able to prevent or delay the progression of IBD, especially because they reach higher concentrations in the gut than in other tissues. However, knowledge of the use of polyphenols in managing human IBD is still scanty, and further clinical studies should afford more solid evidence of their beneficial effects.
TL;DR: This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies.
Abstract: mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signalling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD- 8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.
TL;DR: The molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.
Abstract: The latest advancement in neurobiological research provided an increasing evidence that inflammatory and neurodegenerative pathways play a relevant role in depression. Preclinical and clinical studies on depression highlighted an increased production of inflammatory markers, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α and interferon- α and γ. On the other hand, acute and chronic administration of cytokines or cytokine inducers were found to trigger depressive symptoms. According to the cytokine hypothesis, depression would be due to a stress-related increased production of pro-inflammatory cytokines that, in turn, would lead to increased oxidative and nitrosative brain damage and to indoleamine 2,3 dioxygenase (IDO) induction, with production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and consequent reduced availability of TRP and serotonin (5-HT). Cytokines would also play a role in the onset of the glucocorticoid resistance, underlying the overdrive of the hypothalamic-pituitary-adrenal axis. Therefore, the activation of the inflammatory and neurodegenerative pathways would lead to the brain damage observed in depression through both reduced neurogenesis and increased neurodegeneration. Besides the 5-HT system, other targets, possibly within the I&ND pathways, should be considered for the future treatment of depression: cytokines and their receptors, intracellular inflammatory mediators, IDO, TRYCATs, glucocorticoid receptors, neurotrophic factors may all represent possible therapeutic targets for novel antidepressants. In addition, it should be also clarified the role of the existing anti-inflammatory drugs in the treatment of depression, and those compounds with the anti-inflammatory and anti-oxidative properties should be examined either as monotherapy or adjunctive therapy. In conclusion, the molecular inflammatory and neurodegenerative pathways might provide new targets for antidepressant development and might be crucial to establish a rational treatment of depression aimed, hopefully, to its causal factors.
TL;DR: New findings suggest HIF-1 as a potential medicinal target for the neurodegenerative diseases and its potential neuroprotective roles in Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS).
Abstract: Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. HIF-1, a heterodimer consisting of a constitutively expressed β subunit and an oxygen-regulated α subunit, regulates a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The activity of HIF-1 is controlled by post-translational modifications on different amino acid residues of its subunits, mainly the alpha subunit. Besides in ischemic stroke (see review [1]), emerging evidence has revealed that HIF-1 activity and expression of its down-stream genes, such as vascular endothelial growth factor and erythropoietin, are altered in a range of neurodegenerative diseases. At the same time, experimental and clinical evidence has demonstrated that regulating HIF-1 might ameliorate the cellular and tissue damage in the neurodegenerative diseases. These new findings suggest HIF-1 as a potential medicinal target for the neurodegenerative diseases. This review focuses on HIF-1α protein modifications and HIF-1's potential neuroprotective roles in Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS).
TL;DR: The development of more efficient flavonoid's based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases.
Abstract: The experimental evidences accumulated during last years point out a relevant role of oxidative stress in neurodegeneration As anti-cellular oxidative stress agents flavonoids can act either as direct chemical antioxidants, the classic view of flavonoids as antioxidants, or as modulators of enzymes and metabolic and signaling pathways leading to an overshot of reactive oxygen species (ROS) formation, a more recently emerging concept Flavonoids, a large family of natural antioxidants, undergo a significant hepatic metabolism leading to flavonoid-derived metabolites that are also bioactive as antioxidant agents The development of more efficient flavonoid's based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases On these grounds, we have reviewed the reports on neuroprotection by different classes of flavonoids on cellular cultures and model animals In addition, as they are now becoming valuable pharmacological drugs, due to their low toxicity, the reported adverse effects of flavonoids in model experimental animals and humans are briefly discussed
TL;DR: New hope is emerging for the treatment of OA through selective inhibition of MMP-13 through synthetic compounds of low molecular mass incorporating specific zinc- binding groups, non-zinc-binding groups in this field.
Abstract: Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.
TL;DR: This chemistry will form the basis for a concise discussion of the latest advances in the mechanisms of catecholamine-associated neurotoxicity in neuronal degeneration and the analogies and differences between the central neurotransmitters dopamine and norepinephrine.
Abstract: Aberrant oxidative pathways of catecholamine neurotransmitters, i.e. dopamine and norepinephrine, are an important biochemical correlate of catecholaminergic neuron loss in some disabling neurodegenerative diseases of the elderly, notably Parkinson's disease. In an oxidative stress setting, under conditions of elevated lipid peroxidation, iron accumulation, impaired mitochondrial functioning and antioxidant depletion, catecholamines are oxidatively converted to the corresponding o-quinones, which may initiate a cascade of spontaneous reactions, including intramolecular cyclization, aminoethyl side chain fission and interaction with molecular targets. The overall outcome of the competing pathways may vary depending on contingent factors and the biochemical environment, and may include formation of nitrated derivatives, neuromelanin deposition, generation of chain fission products, conjugation with L-cysteine leading eventually to cytotoxic responses and altered cellular function. In addition, catecholamines may interact with products of lipid peroxidation and other species derived from oxidative breakdown of biomolecules, notably glyoxal and other aldehydes, leading e.g. to tetrahydroisoquinolines via Pictet-Spengler chemistry. After a brief introductory remark on oxidative stress biochemistry, the bulk of this review will deal with an overview of the basic chemical pathways of catecholamine oxidation, with special emphasis on the analogies and differences between the central neurotransmitters dopamine and norepinephrine. This chemistry will form the basis for a concise discussion of the latest advances in the mechanisms of catecholamine-associated neurotoxicity in neuronal degeneration.