Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site

Natural products have continued to drive the development of new chemotherapeutics and elucidation of new biological targets for the treatment of disease. Since Whitesell and Neckers' original discovery that geldanamycin does not directly inhibit v-Src, but instead manifests its biological activity through inhibition of the Hsp90 molecular chaperone, additional natural products and natural product derivatives have been identified and developed to inhibit the Hsp90 protein folding machinery. 17-AAG, a geldanamycin analogue, is currently in clinical trials for the treatment of several types of cancer. Recent work has produced improved radicicol analogues that show promising Hsp90 inhibitory activity in vitro. In addition, chimeric molecules of these two natural products are active in vitro and represent a novel class of Hsp90 inhibitors for cancer treatment. In addition to their chemotherapeutic uses, natural product inhibitors and their derivatives have been utilized to probe the biological mechanisms by which Hsp90 inhibition regulates tumor cell growth. As a consequence of these studies, the molecular chaperones have emerged as an exciting new class of therapeutic targets. This review will highlight the utility of the natural products, geldanamycin and radicicol, as well as improved analogues and the activities exhibited by these compounds against various cancer cell lines.     

Phenolic constituents from the aerial parts ofArtemisia stolonifera

Two acetophenone glycosides, 2,4-dihydroxy-6-methoxy acetophenone 4-O-β-D-glucopyranoside(I), 2,4,6-trihydroxy acetophenone 2-O-β-D-glucopyranoside(II), together with coniferin(III) were isolated from the aerial parts ofArtemisia stolonifera (Max.) Kom. The structures of the compounds were elucidated on the basis of spectroscopic evidence. Compound II was also confirmed as a new phenolic glycoside from natural sources. In addition, compound I induced cytostatic activity of macrophages, while compounds II and III did not.     

Hybrid molecules incorporating natural products: applications in cancer therapy, neurodegenerative disorders and beyond

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.     

Protective effect of Jasonia montana against ethinylestradiol-induced cholestasis in rats

Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. The aim of the present article is to investigate anticholestatic activity of the ethanolic extract of the aerial parts of Jasonia montana against liver cholestasis induced by EE in adult female rats in an attempt to understand its mechanism of action, which may pave the way for possible therapeutic applications. Subcutaneous administration of 100 μg/kg b.w. ethinylestradiol to rats induced hepatocellular cholestasis with a significant decrease in serum cholesterol, bile acids and bilirubin levels as well as in hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) activities and hepatic total, protein-bound and non-protein sulfhydryl groups. Also, treatment with EE produced significant increase in serum Pi-glutathione-s-transferase (Pi-GST), gamma glutamyl transpeptidase (γ-GT) and alpha-glutathione-s-transferase (α-GST) activities as well as serum nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) level and hepatic malondialdehyde (MDA) level as compare to control group. Oral administration of the aerial parts of ethanolic extract at a concentration of 150 mg/kg b.w. daily to rats treated with EE for 15 days showed a significant protection against-induced decrease in serum cholesterol, bile acids and bilirubin levels. The treatment also resulted in a significant increase in hepatic SOD, GPx and GR activities as well as hepatic total, protein-bound and non-protein sulfhydryl groups. In addition, the extract could inhibit serum Pi-GST, γ-GT and α-GST activities as well as reduce serum TNF-α, NO and hepatic MDA as compare to ethinylestradiol treated rats. High content of flavonoids and phenolic compounds was found in ethanolic extract, which may be responsible for free radical activity. The results clearly suggest that the aerial parts of J. montana extract may effectively normalize the impaired antioxidant status in ethinylestradiol (EE)-cholestatic model. Thus the extract may have a therapeutic value in drug-induced biliary cholestasis as well as in hormonal therapy.     

4-Hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) inhibits peroxynitrite-mediated phenol nitration

Peroxynitrite (PN), a very reactive oxidant formed by the combination of superoxide and nitric oxide, appears to play a role in producing tissue damage in a number of inflammatory conditions. Pharmacological scavenging and decomposition of PN within these areas has therapeutic value in several tissue injury models. Recently, we have been interested in nitroxide free radical-containing compounds as possible scavengers of PN decomposition products. Nitroxides can undergo redox reactions to the corresponding hydroxylamine anion or oxoammonium cation in biological systems as shown by its ability to react with superoxide, leading to the formation of hydrogen peroxide and molecular oxygen. We found that 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) inhibits PN-mediated nitration of phenolic compounds in the presence of a large molar excess of PN, suggesting a catalytic-like mechanism. In these experiments, Tempol inhibited PN-mediated nitration over the pH range of 6.5-8.5. This inhibition was specific for nitration and had no effect on hydroxylation. After the inhibition of PN-mediated nitration, Tempol was recovered from the reaction mixtures unmodified. In addition, Tempol was effective in protecting PC-12 cells from death induced by SIN-1, a PN-generating compound. The exact mechanism of Tempol's interaction with PN is not clear; however, we propose that an intermediate in this reaction may be a nitrogen dioxide radical-Tempol complex. This complex could react with water to form either nitrite or nitrate, or with a phenol radical to produce nitrophenol or nitrosophenol products and regenerate the nitroxide.     

Phenolic fractions from Trifolium pallidum and Trifolium scabrum aerial parts in human plasma protect against changes induced by hyperhomocysteinemia in vitro

Elevated concentration of homocysteine (Hcy) in human plasma, defined as hyperhomocysteinemia has been correlated with some diseases, such as cardiovascular, neurodegenerative, and kidney disorders. Homocysteine occurs in human plasma in several forms, including the most reactive form of Hcy – its cyclic thioester – homocysteine thiolactone (HTL), which represents up to 0.29% of plasma total Hcy. It is suggested that Hcy and HTL may also act as oxidants, but various polyphenolic antioxidants are able to inhibit the oxidative damage induced by Hcy or HTL. The aim of our present study was to investigate in vitro oxidative changes in human plasma induced by the model of hyperhomocysteinemia in the presence of the phenolic fractions from selected clovers (Trifolium pallidum and Trifolium scabrum aerial parts). Hyperhomocysteinemia was stimulated by a reduced form of Hcy (final dose 100 μM) or HTL (final dose 1 μM). The aim of our study was also to explain the effect of the phenolic fractions on the coagulation activity of human plasma treated with Hcy and its thiolactone. Tested phenolic fractions significantly inhibited the oxidative stress (measured by the total antioxidant level – TAS) in plasma treated with Hcy or HTL. The phenolic fractions from T. pallidum and T. scabrum also caused a distinct reduction of plasma lipid peroxidation (measured by the level of thiobarbituric acid reactive substance) induced by the model of hyperhomocysteinemia. Moreover, tested fractions modulated the coagulation properties of plasma treated with homocysteine and its thiolactone. It seems that antioxidative activities of the phenolic fractions from T. pallidum and T. scabrum aerial parts may be responsible for their medicinal properties during hyperhomocysteinemia.     

Antioxidant and antibacterial activities of Rumex japonicus HOUTT. Aerial parts

We evaluated total phenolic content, antioxidant activity, reducing power and antibacterial activity of ethanol, hexane, chloroform, ethyl acetate and aqueous extracts of aerial parts of Rumex japonicus HOUTT. The ethyl acetate extract had the highest amount of phenolic compounds. It also exhibited the highest reducing power and antioxidant activity when assayed by the 1,1-diphenyl-2-picrylhydrazyl (DPPH), beta-carotene bleaching and superoxide radical methods. The ethyl acetate extract possessed the strongest antibacterial activity against Bacillus subtilis, B. cereus and E. coli. GC-MS analysis indicated that ethyl acetate extract contained a variety of phenolic compounds. HPLC analysis showed that pyrogallol was the predominant phenolic compound in this extract. Thus, our study verified that the ethyl acetate extract has strong antioxidant and antibacterial activities which are correlated with its high level of phenolic compounds, particularly pyrogallol and pyrocatechin. This extract of R. japonicus aerial parts can be utilized as an effective and safe source of antioxidants.     

Chemistry and bioactivity of Gardenia jasminoides

Gardenia jasminoides, grown in multiple regions in China, was commonly used as a natural yellow dye but has been one of the popular traditional Chinese medicines since the discovery of its biological property a few decades ago. It has been reported that G. jasminoides possess multiple biological activities, such as antioxidant properties, hypoglycemic effect, inhibition of inflammation, antidepression activity, and improved sleeping quality. In this review, our aim was to have a comprehensive summary of its phytochemistry including the extraction, isolation, and characterization of volatiles and bioactive molecules in G. jasminoides, focusing on the two major phytochemicals, genipin and crocin, which possess potent medicinal properties. Furthermore, this study attempted to establish a structure–activity relationship between the two major series of molecules with two pharmcophores and their biological activities, which would serve further exploration of the properties of phytocompounds in G. jasminoides as potential functional foods and medicines.     

Phloroglucinol compounds of therapeutic interest: global patent and technology status

Background: Phloroglucinol compounds, both synthetic as well as natural, have shown a vast array of biological activities. There are a wide range of applications of phloroglucinol compounds in pharmaceuticals, cosmetics, textiles, paints and dyeing industries. Although many of the phloroglucinols have shown promising results in various biological assays, very few have reached clinics. Objective: To compile the patented information on various therapeutically active phloroglucinol molecules, so that technologies used in isolation and activity assessment of these compounds could be unearthed and the compiled information be utilized for further development of these molecules. Methods: The European Patent Office database (official website: espacenet.com) was searched with a keyword “phloroglucinol”. In addition, patents were searched using names of compounds listed in our previous review. Conclusions: This class holds potential for development of molecules in various therapeutic areas. There exist a number of patents on preparations that have phloroglucinol compounds as active ingredient(s). Many such preparations have been tested in vitro and/or in vivo for their efficacy and proven to be active and non-toxic. Commercialization of existing technology on phloroglucinol molecules can yield fruitful results.     

Natural products from cyanobacteria: Exploiting a new source for drug discovery

In the 1990s, the pharmaceutical industry shifted its focus to a combinatorial chemistry approach to fill drug-discovery pipelines; however, more recently there has been renewed interest in natural products as sources of lead compounds. Cyanobacteria are prolific producers of natural products displaying enormous chemical diversity, yet, until recently, exploitation of the genera was hampered by a number of issues related to their handling. With most of these problems now resolved, cyanobacteria have the potential to expand the variety of natural products obtained from microorganisms. The relative disregard in the past of cyanobacteria compared with other microbial sources of natural products, as well as the huge chemical diversity and biological activities of their products, recommend them as an attractive source of novel drugs for use in diverse therapeutic areas.     

Wound healing agents: the role of natural and non-natural products in drug development

Impaired wound healing leads to infection and tissue necrosis. This has spurred the search for wound healing agents derived from natural and non-natural sources. Although natural products are widely used as lead compounds for the design of therapeutic drugs, few studies have looked for potential wound healing compounds in nature. In this review, we briefly discuss each phase of the wound healing process. Examples of natural and non-natural products with wound healing activities are listed, and the structure-activity relationship of fifty one compounds are described. An understanding of how these compounds exert their activities in biological systems is essential for their future development and application as wound healing agents.     

Characterization of phenolic compounds in flowers of wild medicinal plants from Northeastern Portugal

Crataegus monogyna, Cytisus multiflorus, Malva sylvestris and Sambucus nigra have been used as important medicinal plants in the Iberian Peninsula since a long time ago, and are claimed to have various health benefits. This study aimed to determine the phenolic profile and composition of wild medicinal flowers of those species. The analysis was performed by HPLC–DAD–ESI/MS. Flavonoids, and particularly flavonols and flavones, were the main groups in almost all the studied samples. C. multiflorus sample gave the highest levels of total flavonoids (54.5 mg/g dw), being a chrysin derivative the most abundant flavone found (22.3 mg/g dw). C. monogyna revealed the highest concentration in phenolic acids (5.5 mg/g dw) that were not found in C. multiflorus sample; 5-O-caffeoylquinic acid was the most abundant phenolic acid found in the first species, being a procyanidin trimer also found (1.4 mg/g dw). Kaempferol-3-O-rutinoside (0.84 mg/g dw) and quercetin-3-O-rutinoside (14.9 mg/g dw) were the main flavonols present in M. sylvestris and S. nigra, respectively. Due to the well established antioxidant activity of phenolic compounds, the studied wild medicinal flowers could be selected for processing extracts with health-promoting properties or to be incorporate into functional beverages or products with bioactive properties related to oxidative stress.     

Selenium as an emerging versatile player in heterocycles and natural products modification

The diverse pharmacological activities of organoselenium compounds are closely correlated to their ability to scavenge and induce reactive oxygen species (ROS), their intrinsic oxidative properties, and their Se(0) release property. The incorporation of selenium into small molecules, and particularly into heterocycles and natural products, has shown great potential in altering the potency and selectivity of these molecules. Therefore, selenium will play an important role in drug discovery in the near future. We summarize how different organoselenium species affect cellular oxidative stress levels, and try to correlate the structural properties of selenium-containing heterocycles and natural product derivatives to their biological activities and therapeutic applications. We also provide some information to guide the rational design of selenium-containing drugs.     

Antidiabetic and antioxidant activity of hydroxycinnamic acids from Calamintha Officinalis Moench.

This study was undertaken to investigate the antidiabetic and antioxidant activities of crude extracts and pure compounds from the aerial parts of Calamintha officinalis Moench. (Lamiaceae). The aqueous extract showed the promising antidiabetic and antioxidant activities. Based on these findings, the aqueous extract was fractionated on a silica gel column chromatography in a bioassay-guided fractionation affording two known hydroxycinnamic acids showing potent activity (1) rosamarinic acid and (2) caffeic acid. Both rosamarinic acid and caffeic acid exhibited significant activity, even more than the positive control, glibenclamide. The results indicated that Calamintha officinalis aqueous extract and the isolated compounds are potential natural agents for the control of diabetes.     

Enhanced antioxidant and antityrosinase activities of longan fruit pericarp by ultra-high-pressure-assisted extraction

The health benefits of fruits acting against chronic diseases are ascribed to their antioxidant activities which are mainly responsible due to the presence of phenolic compounds. The use of ultra-high-pressure-assisted extraction (UHPE) has shown great advantages for the extraction of these phenolic compounds from longan fruit pericarp (LFP). Studies were carried out to investigate the effects of UHPE at pressures of 200, 300, 400 and 500 MPa on total phenolic contents, extraction yield, antioxidant and antityrosinase activities from LFP. The antioxidant activities of these extracts were analyzed, using various antioxidant models like 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, total antioxidant capacity and superoxide anion radical scavenging activity. Extract from ultra-high-pressure-assisted extraction at 500 MPa (UHPE-500) showed the highest antioxidant activities of all the tested models. In addition, it also showed moderate tyrosinase inhibitory activity. Three phenolic acids, namely gallic acid, ellagic acid, and corilagin were identified and quantified by HPLC. Corilagin content was the highest compared to other phenolic acids identified. UHPE-500 obtained the higher phenolic acid contents compared to other high pressure processing and conventional extractions (CE). Compared with CE, UHPE-500 exhibited good extraction effectiveness in terms of higher extraction yields with high phenolic contents and also with higher antioxidant and antityrosinase activities.     

Carbohydrates in therapeutics

Awareness of the importance of carbohydrates in living systems and medicine is growing due to the increasing understanding of their biological and pharmacological relevance. Carbohydrates are ubiquitous and perform a wide array of biological roles. Carbohydrate-based or -modified therapeutics are used extensively in cardiovascular and hematological treatments ranging from inflammatory diseases and anti-thrombotic treatments to wound healing. Heparin is a well-known and widely used example of a carbohydrate-based drug but will not be discussed as it has been extensively reviewed. We will detail carbohydrate-based and -modified therapeutics, both those that are currently marketed or in various stages of clinical trials and those that are potential therapeutics based on promising preclinical investigations. Carbohydrate-based therapeutics include polysaccharide and oligosaccharide anti-inflammatory, anti-coagulant and anti-thrombotic agents from natural and synthetic sources, some as an alternative to heparin and others which were designed based on known structure-functional relationships. Some of these compounds have multiple biological effects, showing anti-adhesive, anti-HIV and anti-arthrithic activities. Small molecules, derivatives or mimetics of complement inhibitors, are detailed for use in limiting ischemia/ reperfusion injuries. Monosaccharides, both natural and synthetic, have been investigated for their in vivo anti-inflammatory and cardioprotective properties. Modification by glycosylation of natural products, or glycosylation-mimicking modification, has a significant effect on the parent molecule including increased plasma half-life and refining or increasing desired functions. It is hoped that this review will highlight the vast therapeutic potential of these natural bioactive molecules.     

Antimicrobial activity,phenolic profile and role in the inflammation of propolis

Nowadays a great amount of information regarding chemical and biological aspects of bee products is available in the literature, but few data on its therapeutic uses are found. The aim of this study was to evaluate the phenolic profile, the in vitro antimicrobial activity and effect in the hyaluronidase enzyme (widely related with the inflammation process) of propolis harvested in Portugal. The efficacy of three extracts (hydro-alcoholic, methanolic and aqueous) was also compared. It was chosen the hydro-alcoholic extract, because this was the most effective for extracting phenolic compounds. The antimicrobial activity was accessed in Gram-positive and Gram-negative bacteria and yeasts, isolated from different biological fluids and the results were then compared with the obtained for reference microorganisms. The propolis from Bragança was the one that possessed the highest polyphenols’ content. The sample from Beja showed the less significant inhibition of the hyaluronidase enzyme. Concerning the antimicrobial activity, Candida albicans was the most resistant and Staphylococcus aureus the most sensitive. The reference microorganisms were more sensitive than the ones isolated from biological fluids.     

Phenolic Contents and Antioxidant Properties from Aerial Parts of Achyranthes coynei Sant

Aim of the study was to evaluate antioxidant activity and total phenolic content of Achyranthes coynei; an endemic plant used in treatment of several diseases in the same lines that of Achyranthes aspera by traditional practitioners of Belgaum region. Efficiency of extraction methods was studied for aerial parts (leaves, stem, and inflorescence) extracted in methanol using continuous shaking, microwave assisted and ultra sonic extraction technique, by exposing it for different time period. Total phenolic content was measured by Folin-Ciocalteu method and antioxidant activity using 2,2’-diphenyl-1-picryl hydrazyl radical scavenging assay and ferric reducing antioxidant power assay. Extracts of A. coynei revealed highest yield of total phenolic content in continuous shaking method compared to other methods. Significantly higher amount of phenolic content (467.07±23.35 tannic acid equivalent and 360.83±18.04 caffic acid equivalent mg/100 g FW) was estimated at 360 min of continuous shaking extraction. In 2,2’-diphenyl-1-picryl hydrazyl radical scavenging assay and ferric reducing antioxidant power assay, inflorescence and leaf showed highest potential activity, respectively. Stem extracts showed lower yield of total phenolic content and antioxidant activity. Results also showed 2,2’-diphenyl-1-picryl hydrazyl radical scavenging assay had significant correlation with total phenolic content. This is first report of total phenolic content and antioxidant studies in A. coynei.     

Phenolic compounds and biological activities of small-size citrus: Kumquat and calamondin

Kumquat and calamondin are two small-size citrus fruits. Owing to their health benefits, they are traditionally used as folk medicine in Asian countries. However, the research on flavonoids and biological activities of kumquat and calamondin have received less attention. This review summarizes the reported quantitative and qualitative data of phenolic compositions in these two fruits. Effects of maturity, harvest time, various solvent extractions and heat treatment of phenolic compositions, and bioactivities were discussed; distributions of the forms of phenolic compounds existing in kumquat and calamondin were also summarized. Furthermore, biological activities, including antioxidant, antityrosinase, antimicrobial, antitumor, and antimetabolic disorder effects, have also been discussed. Effective phenolic components were proposed for a certain bioactivity. It was found that C-glycoside flavonoids are dominant phenolic compounds in kumquat and calamondin, unlike in other citrus fruits. Up to now, biological activities and chemical characteristics of C-glycoside flavonoids in kumquat and calamondin are largely unknown.