Synthesis and antidiabetic activity of 5,7-dihydroxyflavonoids and analogs

In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7-dihydroxyflavanones and 5,7-dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d, and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7-dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds.     

Synthesis and Antidiabetic Activity of 5,7‐Dihydroxyflavonoids and Analogs

In a study to evaluate the structural elements essential for the antidiabetic activity of flavonoids, we synthesized two series of flavonoids, 5,7‐dihydroxyflavanones and 5,7‐dihydroxyflavones. In a screening for potential antidiabetic activity, most of the flavonoids showed a remarkable in vitro activity, and compounds 1f, 2d , and 3c were significantly more effective than the positive control, metformin. The biological activity was mainly affected by structural modification at the ring B moiety of the flavonoid skeleton. The results suggest that 5,7‐dihydroxyflavonoids can be considered as promising candidates in the development of new antidiabetic lead compounds.     

Centipede venom peptide SsmTX‐I with two intramolecular disulfide bonds shows analgesic activities in animal models

Pain is a major symptom of many diseases and results in enormous pressures on human body or society. Currently, clinically used analgesic drugs, including opioids and nonsteroidal anti‐inflammatory drugs, have adverse reactions, and thus, the development of new types of analgesic drug candidates is urgently needed. Animal venom peptides have proven to have potential as new types of analgesic medicine. In this research, we describe the isolation and characterization of an analgesic peptide from the crude venom of centipede, Scolopendra subspinipes mutilans. The amino acid sequence of this peptide was identical with SsmTX‐I that was previously reported as a specific Kv2.1 ion channel blocker. Our results revealed that SsmTX‐I was produced by posttranslational processing of a 73‐residue prepropeptide. The intramolecular disulfide bridge motifs of SsmTX‐I was Cys1–Cys3 and Cys2–Cys4. Functional assay revealed that SsmTX‐I showed potential analgesic activities in formalin‐induced paw licking, thermal pain, and acetic acid‐induced abdominal writhing mice models. Our research provides the first report of cDNA sequences, disulfide motif, successful synthesis, and analgesic potential of SsmTX‐I for the development of pain‐killing drugs. It indicates that centipede peptide toxins could be a treasure trove for the search of novel analgesic drug candidates. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.     

Recombinant BCG vaccine candidates

Given the variable protective efficacy provided by Mycobacterium bovis BCG (Bacillus Calmette-Guérin), there is a concerted effort worldwide to develop better vaccines that could be used to reduce the burden of tuberculosis. Recombinant BCG (rBCG) are vaccine candidates that offer some potential in this area. In this paper, we will discuss the molecular methods used to generate rBCG, and the results obtained with some of these new vaccines as compared with the conventional BCG vaccine in diverse animal models. Tuberculosis vaccine candidates based on rBCG are promising candidates, and some of them are now being tested in clinical trials.     

Comprehensive review of antimicrobial activities of plant flavonoids

Flavonoids are one of the largest classes of small molecular secondary metabolites produced in different parts of the plant. They display a wide range of pharmacological and beneficial health effects for humans, which include, among others, antioxidative activity, free radical scavenging capacity, coronary heart disease prevention and antiatherosclerotic, hepatoprotective, anti-inflammatory, and anticancer activities. Hence, flavonoids are gaining high attention from the pharmaceutical and healthcare industries. Notably, plants synthesize flavonoids in response to microbial infection, and these compounds have been found to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Antimicrobial action of flavonoids results from their various biological activities, which may not seem very specific at first. There are, however, promising antibacterial flavonoids that are able not only to selectively target bacterial cells, but also to inhibit virulence factors, as well as other forms of microbial threats, e.g. biofilm formation. Moreover, some plant flavonoids manifest ability to reverse the antibiotic resistance and enhance action of the current antibiotic drugs. Hence, the development and application of flavonoid-based drugs could be a promising approach for antibiotic-resistant infections. This review aims to improve our understanding of the biological and molecular roles of plant flavonoids, focusing mostly on their antimicrobial activities.

     

Anti-nociceptive effect of synthesized di-hydroxy flavones: possible mechanism

Renewed interest on the research on the flavonoids is gaining more importance. Earlier literature on flavonoids indicated a significant anti-nociceptive action for flavones and mono-substituted flavones. However, they exhibited a ceiling effect. The present study was undertaken by new synthesizing six disubstituted flavones (DHFs) since poly substituted ones are expected to produce more potent effect. Their anti-nociceptive effect and the role of opioid involvement were studied using acetic acid induced abdominal constriction assay. All the six DHFs administered in elicited a dose related inhibition of abdominal constrictions indicating the presence of the anti-nociceptive response. However, these substances also showed a similar ceiling effect. Like other flavonoid substances, they also utilized opioid pathways. It is suggested that these newly synthesized DHFs can be included along with other flavonoids while attempting clinical trial for analgesic use.     

A review of antimalarial plants used in traditional medicine in communities in Portuguese-speaking countries: Brazil, Mozambique, Cape Verde, Guinea-Bissau, São Tomé and Príncipe and Angola

The isolation of bioactive compounds from medicinal plants, based on traditional use or ethnomedical data, is a highly promising potential approach for identifying new and effective antimalarial drug candidates. The purpose of this review was to create a compilation of the phytochemical studies on medicinal plants used to treat malaria in traditional medicine from the Community of Portuguese-Speaking Countries (CPSC): Angola, Brazil, Cape Verde, Guinea-Bissau, Mozambique and S?o Tomé and Príncipe. In addition, this review aimed to show that there are several medicinal plants popularly used in these countries for which few scientific studies are available. The primary approach compared the antimalarial activity of native species used in each country with its extracts, fractions and isolated substances. In this context, data shown here could be a tool to help researchers from these regions establish a scientific and technical network on the subject for the CPSC where malaria is a public health problem.     

Physiological and pharmacological properties of adenosine: therapeutic implications

Adenosine is a nucleoside which has been shown to participate in the regulation of physiological activity in a variety of mammalian tissues, and has been recognized as a homeostatic neuromodulator. It exerts its actions via membrane-bound receptors which have been characterized using biochemical, electrophysiological and radioligand binding techniques. Adenosine has been implicated in the pharmacological actions of several classes of drugs. A number of studies strongly suggest that the nucleoside may regulate cellular activity in many pathological disorders and, in that respect, adenosine derivatives appear as promising candidates for the development of new therapeutic compounds, such as anticonvulsant, anti-ischemic, analgesic and neuroprotective agents.     

Antimicrobial properties of analgesic kyotorphin peptides unraveled through atomic force microscopy

Antimicrobial peptides (AMPs) are promising candidates as alternatives to conventional antibiotics for the treatment of resistant pathogens. In the last decades, new AMPs have been found from the cleavage of intact proteins with no antibacterial activity themselves. Bovine hemoglobin hydrolysis, for instance, results in AMPs and the minimal antimicrobial peptide sequence was defined as Tyr-Arg plus a positively charged amino acid residue. The Tyr-Arg dipeptide alone, known as kyotorphin (KTP), is an endogenous analgesic neuropeptide but has no antimicrobial activity itself. In previous studies new KTP derivatives combining C-terminal amidation and Ibuprofen (Ib) - KTP-NH(2), IbKTP, IbKTP-NH(2) - were designed in order to improve KTP brain targeting. Those modifications succeeded in enhancing peptide-cell membrane affinity towards fluid anionic lipids and higher analgesic activity after systemic injection resulted therefrom. Here, we investigated if this affinity for anionic lipid membranes also translates into antimicrobial activity because bacteria have anionic membranes. Atomic force microscopy revealed that KTP derivatives perturbed Staphylococcus aureus membrane structure by inducing membrane blebbing, disruption and lysis. In addition, these peptides bind to red blood cells but are non-hemolytic. From the KTP derivatives tested, amidated KTP proves to be the most active antibacterial agent. The combination of analgesia and antibacterial activities with absence of toxicity is highly appealing from the clinical point of view and broadens the therapeutic potential and application of kyotorphin peptides.     

Fungal metabolites: structural diversity as incentive for anticancer drug development

Natural products play an important role in the development of anticancer drugs. To date, predominantly metabolites from plants and bacteria served as lead structures for anticancer agents. Fungal metabolites and derivatives thereof are much less investigated for their potential in cancer therapy. There are, however, some promising candidates derived from fungi in clinical phases I and II studies. This review gives an overview on the role of natural products in cancer therapy and summarises some of the latest results of our group in this area.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Amaryllidaceae isocarbostyril alkaloids and their derivatives as promising antitumor agents

This review covers the isolation, total synthesis, biologic activity, and more particularly the in vitro and in vivo antitumor activities of naturally occurring isocarbostyril alkaloids from the Amaryllidaceae family. Starting from these natural products, new derivatives have been synthesized to explore structure-activity relationships within the chemical class and to obtain potential candidates for preclinical development. This approach appears to be capable of providing novel promising anticancer agents.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Phage display: an important tool in the discovery of peptides with anti-HIV activity

Human immunodeficiency virus (HIV) remains a worldwide health problem despite huge investments and research breakthroughs, and no single drug is effective in killing the virus yet. Among new strategies to control HIV infection, the phage display (PD) technology has become a promising tool in the discovery of peptides that can be used as new drugs, or also as possible vaccine candidates. This review discusses basic aspects of PD and its use to advance two main objectives related to combating HIV-1 infection: the identification of peptides that inhibit virus replication and the identification of peptides that induce the production of neutralizing antibodies. We will cover the different approaches used for mapping and selection of mimotopes, and discuss the promising results of these biologicals as antiviral agents.     

Computational discovery of nanoporous materials for energy- and environment-related applications

ABSTRACT

Our society is currently facing critical energy and environment issues, due to the consistent increase in the usage of fossil fuels and anthropogenic activities. One of the viable solutions is to develop better materials to enable more energy-efficient processes for various applications, including gas separations, energy storage, desalination, etc. Nanoporous materials such as zeolites, metal–organic frameworks (MOFs), and nanoporous graphene have drawn considerable attention as promising candidates in these applications owing to many of their favourable properties. Moreover, the tunability of porous materials results in essentially infinitely large number of possible candidates. While such vast materials space provides great opportunities, it also imposes a significant challenge on the selection of promising candidates. To this end, computational methods, such as molecular simulations, can play an important role in facilitating the discovery and design of optimal materials. In this review, we introduce several computational studies conducted for large-scale materials screenings for gas separations and for the discovery of novel membranes for water filtrations. Furthermore, in light of the importance of molecular force fields for reliable computational predictions, we also discuss some recent developments in this field. Overall, this article discusses the recent advances of computational material discoveries and methodology developments.     

Propionibacterium acnes GehA lipase, an enzyme involved in acne development, can be successfully inhibited by defined natural substances

Propionibacterium acnes, a usual inhabitant of human skin, plays an important role in acne development, related to the production of numerous enzymatic activities involved in the degradation of host molecules. Among these enzymes, P. acnes lipase (GehA, glycerol-ester hydrolase A) has been recognized as one of the major factors in the pathogenesis of acne, being responsible for the hydrolysis of sebum and the release of inflammatory compounds. Anti-acne treatments are based on the use of retinoids or benzoyl peroxide, frequently in combination with antibiotics. However, the low effectiveness of such treatments and the increasing antibiotic resistance has led to the development of alternative therapies such as Kampo formulations, containing traditional herbal drugs. Search for new anti-acne treatments led us to perform the cloning, characterization and inhibition of P. acnes GehA, considered an interesting pharmaceutical target for anti-acne therapies. The genetic, molecular and biochemical properties of the cloned lipase were analysed, and several inhibitor agents were tested, including natural substances like saponins, alkaloids or flavonoids. Among these, the flavonoids (±)-catechin and kaempferol were the most promising candidates for acne treatment, whereas saponins like glycyrrhicic acid and digitonin produced a lower inhibition of the enzyme. No inhibition by alkaloids was found. Therefore, the inhibition caused by (±)-catechin and kaempferol on GehA, together with their wide anti-acne properties and low toxicity, make them very suitable candidates for the treatment of acne and other P. acnes-related diseases.     

Inhibitory effects of flavonoids on aldehyde oxidase activity

Flavonoids are an important group of natural compounds that can interfere with the activity of some enzymes. In this study, effects of various flavonoids on aldehyde oxidase (AO) activity were evaluated in vitro. AO was partially purified from guinea pig liver. The effects of 12 flavonoids from three subclasses of flavon-3-ol, flavan-3-ol and flavanone on the oxidation of vanillin and phenanthridine as substrates of AO and xanthine as a substrate of xanthine oxidase (XO) were investigated spectrophotometrically. Among the 12 flavonoids, myricetin and quercetin were the most potent inhibitors of both AO and XO. In general, the oxidation of vanillin was more inhibited by flavonoids than that of phenanthridine. Almost all of the flavonoids inhibited AO activity more potently than XO, which was more evident with non-planner flavanols. A planner structure seems to be essential for a potent inhibitory effect and any substitution by sugar moieties reduces the inhibitory effects. This study could provide a new insight into AO natural inhibitors with potential to lead to some food-drug interactions.     

Inhibitory effects of flavonoids on aldehyde oxidase activity

Flavonoids are an important group of natural compounds that can interfere with the activity of some enzymes. In this study, effects of various flavonoids on aldehyde oxidase (AO) activity were evaluated in vitro. AO was partially purified from guinea pig liver. The effects of 12 flavonoids from three subclasses of flavon-3-ol, flavan-3-ol and flavanone on the oxidation of vanillin and phenanthridine as substrates of AO and xanthine as a substrate of xanthine oxidase (XO) were investigated spectrophotometrically. Among the 12 flavonoids, myricetin and quercetin were the most potent inhibitors of both AO and XO. In general, the oxidation of vanillin was more inhibited by flavonoids than that of phenanthridine. Almost all of the flavonoids inhibited AO activity more potently than XO, which was more evident with non-planner flavanols. A planner structure seems to be essential for a potent inhibitory effect and any substitution by sugar moieties reduces the inhibitory effects. This study could provide a new insight into AO natural inhibitors with potential to lead to some food-drug interactions.