Showing papers in "Current Medicinal Chemistry in 2018"

Metals and Parkinson's Disease: Mechanisms and Biochemical Processes

Abstract: Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.

Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites.

Abstract: The application of quantum mechanical simulation of chiroptical properties, i.e. electronic circular dichroism (ECD), optical rotation (OR), and vibrational circular dichroism (VCD), to the assignment of the absolute configuration of chiral naturally occurring metabolites of fungal origin, is reviewed. The fundamentals of such chiroptical spectroscopies as well as the specific experimental and computational issues allied to the application of their ab initio calculation is reported. Some examples, related to the use of the ECD, VCD, and OR techniques and highlighting the practical application of the methods, are also described.

Sulphur-containing Amino Acids: Protective Role Against Free Radicals and Heavy Metals.

Abstract: Background Sulphur is an abundant element in biological systems, which plays an important role in processes essential for life as a constituent of proteins, vitamins and other crucial biomolecules. The major source of sulphur for humans is plants being able to use inorganic sulphur in the purpose of sulphur-containing amino acids synthesis. Sulphur-containing amino acids include methionine, cysteine, homocysteine, and taurine. Methionine and cysteine are classified as proteinogenic, canonic amino acids incorporated in protein structure. Sulphur amino acids are involved in the synthesis of intracellular antioxidants such as glutathione and N-acetyl cysteine. Moreover, naturally occurring sulphur-containing ligands are effective and safe detoxifying agents, often used in order to prevent toxic metal ions effects and their accumulation in human body. Methods Literature search for peer-reviewed articles was performed using PubMed and Scopus databases, and utilizing appropriate keywords. Results This review is focused on sulphur-containing amino acids - methionine, cysteine, taurine, and their derivatives - glutathione and N-acetylcysteine, and their defense effects as antioxidant agents against free radicals. Additionally, the protective effects of sulphur-containing ligands against the toxic effects of heavy and transition metal ions, and their reactivation role towards the enzyme inhibition are described. Conclusion Sulphur-containing amino acids represent a powerful part of cell antioxidant system. Thus, they are essential in the maintenance of normal cellular functions and health. In addition to their worthy antioxidant action, sulphur-containing amino acids may offer a chelating site for heavy metals. Accordingly, they may be supplemented during chelating therapy, providing beneficial effects in eliminating toxic metals.

Coating Matters: Review on Colloidal Stability of Nanoparticles with Biocompatible Coatings in Biological Media, Living Cells and Organisms.

Abstract: Within the last two decades, the field of nanomedicine has not developed as successfully as has widely been hoped for. The main reason for this is the immense complexity of the biological systems, including the physico-chemical properties of the biological fluids as well as the biochemistry and the physiology of living systems. The nanoparticles' physicochemical properties are also highly important. These differ profoundly from those of freshly synthesized particles when applied in biological/living systems as recent research in this field reveals. The physico-chemical properties of nanoparticles are predefined by their structural and functional design (core and coating material) and are highly affected by their interaction with the environment (temperature, pH, salt, proteins, cells). Since the coating material is the first part of the particle to come in contact with the environment, it does not only provide biocompatibility, but also defines the behavior (e.g. colloidal stability) and the fate (degradation, excretion, accumulation) of nanoparticles in the living systems. Hence, the coating matters, particularly for a nanoparticle system for biomedical applications, which has to fulfill its task in the complex environment of biological fluids, cells and organisms. In this review, we evaluate the performance of different coating materials for nanoparticles concerning their ability to provide colloidal stability in biological media and living systems.

Analytical and Preparative Scale Separation of Enantiomers of Chiral Drugs by Chromatography and Related Methods.

Abstract: While the amino acids, enzymes and hormones are chiral, chirality plays significant role in the life of plants, animals, as well as the human being Chirality of molecules is important in various industries, such as pharmaceutical, agricultural, food, electronics, etc Chiral drugs may have different bioavailability, distribution, biotransformation and excretion, as well as quantitatively and/or qualitatively different pharmacological or toxic properties Enantiomerically pure chiral drugs have been increasingly developed for the pharmaceutical market due to their superiority from the viewpoints of potency and safety This is supported by the development of new methods for enantioselective production of the chiral compounds, as well as by the capability of the enantioselective analytical methods to allow a detection and quantification of minor enantiomeric impurity in the presence of another enantiomer in a large excess The aim of the present review is to provide a short summary of the basic principles of chiral separations on an analytical and preparative scale In addition, some selected applications for analytical techniques, such as gas chromatography, supercritical fluid chromatography, high performance liquid chromatography, capillary electrophoresis and capillary electrochromatography for the separation of enantiomers of chiral pharmaceuticals published in the last two years are also discussed

Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer's Disease: An Update.

Abstract: Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases.

Abstract: Background Kidney disease is a serious problem that adversely affects human health, but critical knowledge is lacking on how to effectively treat established chronic kidney disease. Mounting evidence from animal and clinical studies has suggested that Vitamin D Receptor (VDR) activation has beneficial effects on various renal diseases. Methods A structured search of published research literature regarding VDR structure and function, VDR in various renal diseases (e.g., IgA nephropathy, idiopathic nephrotic syndrome, renal cell carcinoma, diabetic nephropathy, lupus nephritis) and therapies targeting VDR was performed for several databases. Result Included in this study are the results from 177 published research articles. Evidence from these papers indicates that VDR activation is involved in the protection against renal injury in kidney diseases by a variety of mechanisms, including suppression of RAS activation, anti-inflammation, inhibiting renal fibrogenesis, restoring mitochondrial function, suppression of autoimmunity and renal cell apoptosis. Conclusion VDR offers an attractive druggable target for renal diseases. Increasing our understanding of VDR in the kidney is a fertile area of research and may provide effective weapons in the fight against kidney diseases.

Promising Targets in Anti-cancer Drug Development: Recent Updates

Abstract: Cancer is a multifactorial disease and its genesis and progression are extremely complex. The biggest problem in the anticancer drug development is acquiring of multidrug resistance and relapse. Classical chemotherapeutics directly target the DNA of the cell, while the contemporary anticancer drugs involve molecular-targeted therapy such as targeting the proteins possessing abnormal expression inside the cancer cells. Conventional strategies for the complete eradication of the cancer cells proved ineffective. Targeted chemotherapy was successful in certain malignancies however, the effectiveness has often been limited by drug resistance and side effects on normal tissues and cells. Since last few years, many promising drug targets have been identified for the effective treatment of cancer. The current review article describes some of these promising anticancer targets that include kinases, tubulin, cancer stem cells, monoclonal antibodies and vascular targeting agents. In addition, promising drug candidates under various phases of clinical trials are also described. Multi-acting drugs that simultaneously target different cancer cell signaling pathways may facilitate the process of effective anti-cancer drug development.

Stimuli Responsive Nanoparticles for Controlled Anti-cancer Drug Release.

Abstract: Conventional drugs used for cancer chemotherapy have severe toxic side effects and show individually varied therapeutic responses. The convergence of nanotechnology, biology, material science and pharmacy offers a perspective strategy for cancer chemotherapy. Nanoparticles loaded with anti-cancer drug have been designed to overcome the limitations associated with conventional drugs, several nanomedicines have been approved by FDA and shown good performances in clinical practice. However, the therapeutic efficacies cannot be enhanced. Taking this into account, stimuli responsive nanoparticles present the ability to enhance therapeutic efficacy and reduce side effects. In this review, we systematically summarized the recent progresses of controlled anti-cancer drug release systems based on nanoparticles with different stimuli response including pH, temperature, light, redox and others. If the achievements of the past can be extrapolated into the future, it is highly likely that responsive nanoparticles with a wide array of desirable properties can be eventually developed for safe and efficient cancer therapy.

The Development of Biologically Important Spirooxindoles as New Antimicrobial Agents.

Abstract: BACKGROUND Antibiotic resistance is one of the biggest threats to global health today, leading to higher medical costs and increased mortality. Because of the emergence and rapid spread of new resistance mechanisms globally, a growing number of infections are becoming harder to treat as the antibiotics used to treat them become less effective. Therefore, the development of new effective antimicrobial agents is still urgently needed. In last decades, a large number of structurally novel spirooxindoles have been synthesized mainly based on the ylide intermediates generated in situ and further assessed for their antimicrobial activity against different types of bacteria, leading to the discovery of some potent lead compounds with antimicrobial potentials. OBJECTIVE The aim of this review to submarize recent advances on the synthesis, structure- activity relationship studies (SARs) and antimicrobial activity of spirooxindoles. METHODS Peer-reviewed research work on spirooxindoles with antimicrobial activity were downloaded from bibliographic databases and analyzed based on their chemoptypes. RESULTS 50 papers were retrieved from the literature databases, of which 20 papers described the synthesis and antimicrobial activity of spirooxindoles. CONCLUSION This review highlights the importance of spirooxindoles as potential antimicrobial agents. The antimicrobial activity of spirooxindoles against different types of bacteria is less studied, mainly centering on primary antimicrobial assessment, some of these compounds have showed interesting antimicrobial activity. However, the current study is only limited to primary antimicrobial assessment, no detailed modes of action are investigated.

The Role of Hydrogen Sulfide and H2S-donors in Myocardial Protection Against Ischemia/Reperfusion Injury.

Abstract: Hydrogen sulfide (H2S), previously known only as a toxic agent, in the last decades has been recognized as an important endogenous gasotransmitter, playing a key role in the homeostasis of the cardiovascular system. In the last years, the growing evidence about a protective role exhibited by H2S against myocardial ischemia/reperfusion (I/R), led to an increasing interest for the possible mechanism of action accounting for the H2S cardioprotective effect, and to the discovery of the involvement of several targets. Currently, many mechanisms of action have been proposed and verified through in vitro and in vivo models of I/R injury, such as the anti-inflammatory or the anti-oxidant ones, or mechanisms of Ssufhydration able to modify proteins such as ion channels. Particular attention was focused on the mitochondrial preservation and on anti-apoptotic mechanisms, and finally even a pro-angiogenesis effect has been described. At the same time, the design, the development and the pharmacological characterization of moieties able to release H2S, employed alone as H2S-donor, or conjugated with another drug in hybrid molecules, led to the production of novel chemical entities in the panorama of cardioprotective drugs.

Overview of Cantharidin and its Analogues

Abstract: Background Cantharidin has been categorized as highly toxicant in Chinese medicine. But cantharidin can efficiently treat different types of diseases, such as molluscum contagiosum. While cantharidin is quite useful, unfortunately, due to its side effects, increasing regulations have limited access to this useful therapeutic option. Cantharidin's toxic effects have caused it to fall into disuse for most legitimate medical purposes. Although cantharidin generates effects and its advantages must be realized. Recently, cancer affects people's life more and more. Because cantharidin can treat some cancers, so solutions must be used to reduce side effects. This review aims to describe some its analogues, several efficient methods to inhibit the side effects of cantharidin and pharmacogenomics of cantharidin. Methods We searched for research about cantharidin by entering the database. Then evaluated these papers and analyzed their founding, solution, mechanism, etc., and targeted to screen the papers related to the content of our research, and then sorted them out in accordance with the solution, mechanism research and other content. Finally, these content was unified into a framework. Results Some cantharidin's analogues were found that they show some similar functions to cantharidin and we found that norcantharidin, acylthiourea derivatives, cantharidinamides, anhydride-modified derivatives and other derivatives have less side effects. The modified cantharidin analogues reduce toxicity in hepatocytes. Cantharidin consists of a six-ring and a five-ring, the moiety of oxygen on the six-ring and the anhydride section exhibit biochemical activity. Protein phosphatases are associated with many cellular processes including apoptosis, cell cycle progression and so on. Cantharidin can cause apoptosis and double-stand breakage of DNA. Cantharidin and norcantharidin can efficiently inhibit the activity of mammalian and plant protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) in vivo. Cantharidin inhibits PP5 at the nanomolar level with an IC50 value of 600 nM. PP5 can manage the cellular survival, death, proliferation and other some intracellular biological activities in mammals. After cantharidin's treatment, the level of EtPP5 mRNA expression was downregulated. Their also can be used to inhibit the Glutathione S-transferases (GSTs), angiogenesis and the expression of A549 human lung cancer cells, trigger eryptosis and induced bladder cancer cell apoptosis. We found that using Vitamin C and ginsenosides and translating cantharidin into nanoparticles can minimize the cantharidin side effects in the patients. Conclusion Cantharidin can inhibit various tumor cell lines. Cantharidin causes both DNA single- and double- strand breaks and induces apoptosis. Although cantharidin shows some toxicity for human, its anti-cancer effects should be taken seriously. Several viable methods can help solve this problem. The most important pharmacogenomics of cantharidin is that cantharidin can inhibit PPs, because PPs are associated with many cellular processes. This prospect is very broad and needs to continue studying.

SIRT1 as a Therapeutic Target in Diabetic Complications.

Abstract: Background Sirtuin1 is an epigenetic enzyme involved in histone and nonhistone protein deacetylation. It acts primarily as a metabolic sensor, which responses to changing energy status by deacetylating crucial transcription factors and cofactors. In this way, Sirtuin1 regulates mitochondrial function and biogenesis, oxidative stress, inflammation, apoptosis and cellular senescence. Disturbance of all of these phenomena promotes the pathogenesis of diabetic complications. These disorders are inseparably connected with chronic hyperglycemia, which possesses a strong epigenetic determinant. Objective To summarize the contemporary knowledge regarding the role of Sirtuin1 in the development, progression and therapy of diabetic complications. Methods We extensively searched literature describing the importance of Sirtuin1 in pathophysiology and treatment of all kinds of diabetic complications till September 2017. We focused on the examples of synthetic and natural compounds-mediated Sirtuin1 upregulation along with Sirtuin1-associated epigenetics. Results Reduction of Sirtuin1 is implicated in endothelial dysfunction and metabolic memory, underlying the development of micro- and macrovascular complications. Declined Sirtuin1 also participates in diabetic testicular and erectile dysfunction. Sirtuin1 is elevated by naturally occurring anti-oxidant and anti-inflammatory compounds such as resveratrol, trans-δ-viniferin, vitamin D and more. Similarly, Sirtuin1 level increases after treatment with standard antihyperglycemic (metformin, exenatide, liraglutide), antihypertensive (sartans), lipid-lowering (fibrates, statins) and anticoagulant (fidarestat) drugs. Regarding epigenetics, a number of miRNAs trigger Sirtuin1 decrease, which further contributes to histone acetylation of Sirtuin1-regulated and relevant for diabetes genes. Conclusion Evidence strongly suggest that Sirtuin1 upregulation may serve as a potent therapeutic approach against development and progression of diabetic complications.

Bioactive Metabolites from Pathogenic and Endophytic Fungi of Forest Trees.

Abstract: Background Fungi play an important role in terrestrial ecosystems interacting positively or negatively with plants. These interactions are complex and the outcomes are different depending on the fungal lifestyles, saprotrophic, mutualistic or pathogenic. Furthermore, fungi are well known for producing secondary metabolites, originating from different biosynthetic pathways, which possess biological properties of considerable biotechnological interest. Among the terrestrial ecosystems, temperate forests represent an enormous reservoir of fungal diversity. This review will highlight the goldmine of secondary metabolites produced by pathogenic and endophytic fungi of forest trees with focus on their biological activities. Methods A structured search of bibliographic databases for peer-reviewed research literature was undertaken using a research discovery application providing access to a large and authoritative source of references. The papers selected were examined and the main results were reported and discussed. Results Two hundred forthy-one papers were included in the review, outlined a large number of secondary metabolites produced by pathogenic and endophiltic fungi and their biological activities, including phytotoxic, antifungal, antioomycetes, antibacterial, brine shrimp lethality, mosquito biting deterrence and larvicidal, cytotoxic, antiproliferative and many other bioactivities. Conclusion The findings of this review confirm the importance of secondary metabolites produced by pathogenic and endophytic fungi from forest plants growing in temperate regions as an excellent prospects to discover compounds with new bioactivities and mode of actions. In addition, the potential of some metabolites as a source of new drugs and biopesticides is underlined.

VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apoptosis

Abstract: The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane protein, functions as a mitochondrial governor, controlling transport of metabolites in and out of the mitochondria and energy production, while also coordinating glycolysis and oxidative phosphorylation (OXPHOS). . VDAC1 plays a key role in mitochondria-mediated apoptosis by functioning in the release of apoptotic proteins located in the inter-membranal space (IMS) and due to its association with pro- and anti-apoptotic proteins. Thus, VDAC1 is considered as a promising target for controlling apoptosis. This review provides insight into the central role of VDAC1 in mammalian cell life and death and emphasizes VDAC1 function in apoptosis, focusing on VDAC1 oligomerization as an important step in the intrinsic apoptosis pathway involving mitochondria. Accumulated evidence suggests that VDAC1 oligomerization leads to the formation of a large pore that allows the passage of proteins, like cytochrome c (Cyto c). Here, we focus on the mechanism leading to VDAC1 oligomerization, presenting evidence for the relationship between VDAC1 expression levels and induction of apoptosis. Moreover, we present evidence showing that almost all apoptosis stimuli induce VDAC1 over-expression and suggest that these high levels of VDAC1 shift VDAC from a monomeric to an oligomeric assembly, corresponding to the Cyto c release channel. Several compounds or conditions inducing apoptosis also induce VDAC1 over-expression leading to VDAC1 oligomerization, such as cyathin-R, cisplatin and selenite, are presented. Likewise, VDAC1-interacting molecules, such as 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), diphenylamine-2-carboxylate (DPC), ruthenium red and VBIT, that inhibit VDAC1 oligomerization and apoptosis are also presented. VDAC1 oligomerization as a potential target for controlling apoptosis, specifically using drugs to induce apoptotic cell death in cancer and inhibit apoptosis in neurodegenerative diseases, as well as possible VDAC1-based therapeutic applications, are highlighted.

Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies.

Abstract: Background The spirocyclic compounds have always aroused a great interest because this motif is present as structural core in a number of natural products and bioactive compounds. In particular, the spirolactone moiety has been recognized in a wide array of natural and non-natural scaffolds showing a variety of useful pharmacological properties. Methods Extensive literature search using SciFinder (Databases: CA Plus, CAS Registry, CAS React, Chemlist, Chemcat and Medline) and Web of Science (Database: Web of Science Core Collection) was conducted. Results Nowadays, many efforts are being devoted to the discovery of new natural products containing the promising spirolactone framework and to the disclosure of the potential bioactivities of these chemical entities. Moreover, the medicinal relevance of many spirolactones makes these scaffolds attractive targets for the design and development of innovative and efficient synthetic strategies, enabling the construction of complex and variably substituted products. Conclusion This review gives an overview on the recent advances in the spirolactones field, in terms of new compounds isolated from natural sources, recently determined bioactivity profiles and innovative synthetic approaches. The collected data demonstrate the key role played by spirolactones in medicinal chemistry and the great attention still devoted by the scientific community to these compounds.

Interactions of VDAC with Proteins Involved in Neurodegenerative Aggregation: An Opportunity for Advancement on Therapeutic Molecules.

Abstract: BACKGROUND The Voltage Dependent Anion Channel (VDAC) proteins represent the most important pore-forming proteins of the mitochondrial outer membrane, directly involved in metabolism and apoptosis regulation Literature has highlighted a key role of VDACs in mitochondrial dysfunction typical of many neurodegenerative disorders In particular, the principal isoform VDAC1 represents the main mitochondrial docking site of many misfolded proteins, such as amyloid β and Tau in Alzheimer's disease, α-synuclein in Parkinson's disease and several SOD1 mutants in Amyotrophic Lateral Sclerosis The interaction of misfolded proteins with VDAC1 has a strong impact on both cellular bioenergetics and apoptosis' pathways alteration Therefore, VDACs represent a promising therapeutic target in neurodegeneration OBJECTIVE This review summarizes the roles of VDAC isoforms, and particularly of VDAC1, in the most common neurological disorders and analyzes in detail molecules and peptides available so far, able to interact and modulate VDAC1 in any considered pathological condition CONCLUSION This review offers a description of the most promising therapeutic strategies acting on VDAC1, for the treatment of neurodegenerative diseases

Nanoparticles for SPECT and PET Imaging: Towards Personalized Medicine and Theranostics.

Abstract: Background PET and SPECT imaging methods can be of excellent assistance for the development of new nanoparticle drug delivery systems, and at the same time, these investigations also offer the opportunity to produce exceptional new diagnostic and therapeutic radiopharmaceuticals, as well. With a multifunctional, nano-scaled drug delivery system, the diagnostic (imaging) methods and the therapy (delivering drugs or beta-emitter radionuclides) can be carried out using the same biological and pharmacological mechanisms. By combining therapy and diagnostics in one method or in one specifically targeted nanoparticle system, we can product theranostic pharmaceuticals, and its applications are important elements of personalized medicine. Objectives This review takes a short historical look back to the radiocolloids, the great ancestors of (radiolabeled) nanoparticles and then describes the general features of current types of PET and SPECT imaging associated nanoparticle-based products and key radiolabeling methods; entering into details of potential prospective challenges related to radiotheranostic approaches and imaging guided therapy.

Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy.

Abstract: Background Cancer chemotherapy is limited by severe side effects due to unspecific cytotoxic activity of currently used therapeutics. In order to minimize these unwanted effects, several approaches have been taken, relying on the use of light to activate drugs. As light can be delivered with a very high spatiotemporal resolution, this technique is a promising strategy to selectively activate cytotoxic drugs at their site of action and thus to improve the tolerability and safety of chemotherapy. Objective This review summarizes different approaches towards photoactivated chemotherapy and identifies its challenges and opportunities. Results The respective papers were summarized and evaluated in terms of their phototherapeutic indices and the wavelength needed for activation. First, the design, synthesis and/or evaluation of photoactivated metal complexes including platinum- , ruthenium-, and rhodium-complexes is described. Next, photocaged metal complexes and photoacaged organic chemotherapeutics are reported, with a wide range of cytotoxicity mechanisms. The final part includes, examples of photoswitchable drugs for cancer therapy. Some designs, especially metal complexes, stand out due to their very high phototherapeutic index (g 1880) but the common drawback of light-responsive metal complexes and organic chemotherapeutics is the irreversibility of activation. Photoswitchable drugs, however, address this challenge. Nevertheless, the need of UV light for their activation still limits their application. Conclusion The field of photoactivated cancer chemotherapy is rapidly growing and already includes very promising approaches with designs providing high phototherapeutic indices and also NIR or visible light-activatable drugs.

Natural Products from Deep-Sea-Derived Fungi ̶ A New Source of Novel Bioactive Compounds?

Abstract: Background Over the last two decades, deep-sea-derived fungi are considered to be a new source of pharmacologically active secondary metabolites for drug discovery mainly based on the underlying assumption that the uniqueness of the deep sea will give rise to equally unprecedented natural products. Indeed, up to now over 200 new metabolites have been identified from deep-sea fungi, which is in support of the statement made above. Results This review summarizes the new and/or bioactive compounds reported from deepsea- derived fungi in the last six years (2010 - October 2016) and critically evaluates whether the data published so far really support the notion that these fungi are a promising source of new bioactive chemical entities.

Flavonoids in the Treatment of Alzheimer’s and Other Neurodegenerative Diseases

Abstract: Flavonoids are phytochemicals present in almost all terrestrial plants and, as a consequence, in plant-based foods, and thus consumed by humans through diet Recent evidences suggest that several flavonoids have positive effects against dementia and Alzheimer's disease, reversing age-related declines in neurocognitive performances In this review, we provide a general classification of natural and synthetic flavonoids, a description of their physico-chemical properties, in particular their redox properties and stability, and an extensive overview about their biological activities and structure-activity relationship in the field of neurodegenerative diseases In addition, a section will be dedicated to the synthetic strategies for the preparation of bioactive derivatives This information will be essential for the design and development of new drugs that can improve brain functions

Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013-2016): Opportunities and Challenges.

Abstract: Combinations of antiretroviral drugs are successfully used to treat HIV-infected patients. However, drug resistance is a major problem that makes discovery of new antiretroviral drugs an ongoing priority. The ribonuclease H (RNase H) activity of the HIV-1 reverse transcriptase catalyzes the selective hydrolysis of the RNA strand of RNA:DNA heteroduplex replication intermediates, and represents an attractive unexploited target for drug development. This review reports on recent progress in the characterization of HIV-1 RNase H inhibitors from 2013 to 2016, describing their chemical structures, structureactivity relationship and binding modes. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of RNase H inhibitors.

Anti-Cancer Compounds Targeted to VDAC: Potential and Perspectives.

Abstract: Background VDAC (Voltage-Dependent Anion selective Channel) is a small family of abundant pore-forming proteins located in the outer mitochondrial membrane. Their role range from the most intuitive, the formation of a hydrophilic conduit through the membrane thanks to its beta-barrel structure, to less understood functions that make them essential actors in the cross-talk between the bioenergetics metabolism and the cytosol components. Due to this localization, VDAC1, in particular, has been reported to be involved in apoptosis, Hexokinase and tubulin binding, and in the Warburg effect. For these reasons, an involvement of VDAC in cancer is considered consequential and a number of compounds have been proposed and used in experimental trials to demonstrate the efficacy of molecules affecting the functions of VDAC. Objectives In this work, we thus survey the literature describing drug compounds acting on the cancerous proliferation through VDAC. Three main categories have been assigned: molecules acting on the VDAC-Hexokinase binding, molecules directly inhibiting the VDAC conductance, molecules affecting the expression levels of the VDAC gene. The application of biological peptides for this purpose is also considered. Conclusion Since the knowledges about the functional properties of VDAC protein are still insufficient, VDAC as a pharmacological target in the fight against cancer is still a very open, but very promising, field.

Bovine Serum Albumin as a Versatile Platform for Cancer Imaging and Therapy

Abstract: Background Due to the good biocompatibility, biodegradability, facile surface functionalization and high water solubility, Bovine serum albumin has gain increasing attention in the nanomedicine. Objective Despite there are many reviews on albumin based nanoparticles, most of them focus on one aspect of the albumin functionality, e.g., drug delivery, cancer theranostics or half-life extension in vivo. This review aims to comprehensively summary bovine serum albumin as a versatile platform in the applications of cancer imaging and therapy. Methods We review the extensive applications of bovine serum albumin in drug carrier, surface engineering and biomimetic synthesis for cancer imaging and therapy. Conclusion Based on the studies reviewed, variety of in vitro and in vivo studies show good performance of bovine serum albumin as the drug carrier, surface modification agent and biomimetic template in cancer imaging and therapy. Nevertheless, there are still some issues to be solved, e.g., the technological parameters for enhancing the drug loading efficiency and controlling drug release, optimizing surface modification process to provide more stable nanoagents, investigation of the biomimetic mechanism, in-depth study of their toxicity, further exploring their bioapplications, etc.

A2A Adenosine Receptor Agonists and their Potential Therapeutic Applications. An Update.

Abstract: Background Adenosine is an endogenous purine nucleoside, which mediates a variety of important biological processes and diseases, such as vasodilation, inflammation, cancer, wound healing, ischemia reperfusion injury, Parkinson disease, infectious diseases, and other CNS disorders. Particularly important are the A2A receptors that have been expressed in the lung, liver, heart, cardiovascular tissues, leukocytes, neutrophils, and endothelial cells. This review provides an update of the latest A2A receptor agonists developed in the period 2005-2017, their selectivity regarding other adenosine receptors and their potential therapeutic applications. Methods I have conducted an extensive search from the most common bibliographic databases for critically review the most recent works on the A2A receptor agonists and their therapeutic applications in inflammation, asthma and chronic obstructive pulmonary disease, myocardial perfusion imaging, sepsis, rheumatoid arthritis, and wound healing, among others. Results In the last decade, a great deal of effort has been devoted to develop adenosine receptor agonists and antagonists for treatment of a number of diseases. Thus, for A2A receptor agonists more than 130 papers and reviews have been found, many of them highlighting the usefulness of these compounds in the field. Conclusions Although so far many of the A2A receptor agonists have failed in clinical trials due to their side effects, some of them have been approved for protection against cardiac ischemia-reperfusion injury and anemia. The recently reported crystal structure of the human A2A receptor in complex with the agonist UK-432097 is a fundamental keystone for the development of new and selective A2A ligands with new therapeutic applications.

Biotechnological Production of Pharmaceuticals and Biopharmaceuticals in Plant Cell and Organ Cultures.

Abstract: Background: Plant biofactories are biotechnological platforms based on plant cell and organ cultures used for the production of pharmaceuticals and biopharmaceuticals, although to date only a few of these systems have successfully been implemented at an industrial level. Metabolic engineering is possibly the most straightforward strategy to boost pharmaceutical production in plant biofactories, but social opposition to the use of GMOs means empirical approaches are still being used. Plant secondary metabolism involves thousands of different enzymes, some of which catalyze specific reactions, giving one product from a particular substrate, whereas others can yield multiple products from the same substrate. This trait opens plant cell biofactories to new applications, in which the natural metabolic machinery of plants can be harnessed for the bioconversion of phytochemicals or even the production of new bioactive compounds. Synthetic biological pipelines involving the bioconversion of natural substrates into products with a high market value may be established by the heterologous expression of target metabolic genes in model plants. Objective: To summarize the state of the art of plant biofactories and their applications for the pipeline production of cosme-, pharma- and biopharmaceuticals. Results: In order to demonstrate the great potential of plant biofactories for multiple applications in the biotechnological production of pharmaceuticals and biopharmaceuticals, this review broadly covers the following: plant biofactories based on cell and hairy root cultures; secondary metabolite production; biotransformation reactions; metabolic engineering tools applied in plant biofactories; and biopharmaceutical production.

Polymer Conjugated Gold Nanoparticles in Biomedical Applications.

Abstract: Background Research interest on the properties of polymer conjugated gold nanoparticle (GNP) in biomedicine is rapidly rising because of the extensive evidences for their unique properties. In the field of biomedicine, GNPs have been widely used because of their inertness and low levels of cytotoxicity. Therefore, when exposed to cells, they are less prone to exert damaging effects. GNPs are capable of being functionalized as desired and are ideal as they do not encourage undesired side reactions that might counter react with the intention of the functionalization. Biofouling is an occurrence that takes place at cellular and biological molecular level, binds non-specifically on the detection surface and forms a wrong output. This undesired incidence can be avoided by conjugating the surface of biomolecules with polymers. Densely packed repeating chains of polymers such as polyethylene glycol are capable of decreasing non-specific reactions. Applications of polymer conjugated GNPs in the field of biomedicine are as biosensors, delivery and therapeutic agents. Conclusion Therefore, the properties and applications of polymer conjugated GNPs are studied widely as overviewed here.

Natural Terpenoids Against Female Breast Cancer: A 5-year Recent Research.

Abstract: Background The approval of Taxol® in 1993 marked the great entrance of terpenoids in the anti-cancer area and this drug is still highly important in the treatment of refractory ovarian, breast and other cancers. Over decades, other prominent natural terpenoids have become indispensable for the modern pharmacotherapy of breast cancer. However, given the rapid evolution of drug resistance, effective treatments for advanced breast cancers requiring cytotoxic chemotherapy represent a major unmet clinical need. Therefore, innovative agents effective in long-term chemotherapy are urgently needed. Objective This review examines recent advances/research about natural terpenoids, and their mechanisms against female breast cancer over the period covering January 1st, 2012 to December 31st, 2016. Results Carcinogenesis constitutes a multistep process wherein each stage is characterized by distinct phenotypic changes. Numerous chemicals recorded in this review have been shown to significantly inhibit proliferation, migration, apoptosis resistance, tumor angiogenesis or metastasis in different breast cancer cells/tumours in vitro and in vivo. Targeting simultaneously several or all these aspects/steps of cancer progression could be an advantage. In line with this, phytochemicals such as thymoquinone (8), costunolide (46), tanshinone IIA (132), triptolide (136), cucurbitacin B (179), celastrol (226) and lycopene (238) had caught our attention. Conclusion These compounds appear to be promising to overcome breast cancer treatment failure. However, despite the interesting activities, additional preclinical investigations are needed in further breast cancer cell/tumor models in vitro and in vivo.

Surface-bioengineered Gold Nanoparticles for Biomedical Applications

Abstract: The conjugation of gold nanoparticles (AuNPs) with biomolecules could create many outstanding biofunctions for the surface-functionalized nanoparticles and extend their biomedical applications. In this review, we summarize the recent advances in the surface bioengineering of AuNPs with biomolecules, such as DNA, proteins, peptides, and biopolymers, in which the details on the structure, functions, and properties of surface- bioengineered AuNPs are discussed. In addition, the surface-biofunctionalization of AuNPs for biomedical applications like biosensing, bioimaging, drug delivery, and tissue engineering are introduced. It is expected that this work will be very helpful for readers to understand the surface functionalization and engineering techniques for various metallic nanoparticles and design novel biomaterials for biomedical applications.

Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry

Abstract: The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics