Diana C. G. A. Pinto

SYNTHESIS AND MOLECULAR STRUCTURE OF 3-(2-BENZYLOXY-6-HYDROXYPHENYL)-5-STYRYLPYRAZOLES. REACTION OF 2-STYRYLCHROMONES AND HYDRAZINE HYDRATE

Abstract 3-(2-Benzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles 7a-e were prepared from the reaction of 2-styrylchromones and hydrazine hydrate. 3-(2-Benzyloxy-6-hydroxyphenyl)-5-(2-phenylethyl)-pyrazoles 8a,d,e and 3-(2-benzyloxy-β,6-dihydroxystyryl)-5-aryl-2-pyrazolines 9a-e were also obtained as by-products. The crystal and molecular structure of two 3-(2-benzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles 7a,b have been determined by X-Ray analysis. Although the substitution of an hydrogen by a methyl group on the double bond of the styryl moiety seems to be a minor perturbation, it produces drastic changes in the crystal packing where only one conformer is present. The OH group is involved as donor of an intramolecular hydrogen bond and the NH group is responsible for the formation of chains via intermolecular hydrogen bonds.

The genus Inula and their metabolites: from ethnopharmacological to medicinal uses.

ETHNOPHARMACOLOGICAL RELEVANCE The genus Inula comprises more than one hundred species widespread in temperate regions of Europe and Asia. Uses of this genus as herbal medicines have been first recorded by the Greek and Roman ancient physicians. In the Chinese Pharmacopoeia, from the 20 Inula spp. distributed in China, three are used as Traditional Chinese medicines, named Tumuxiang, Xuanfuhua and Jinfeicao. These medicines are used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. Moreover, Inula helenium L. which is mentioned in Minoan, Mycenaean, Egyptian/Assyrian pharmacotherapy and Chilandar Medical Codex, is good to treat neoplasm, wound, freckles and dandruff. Many other Inula spp. are used in Ayurvedic and Tibetan traditional medicinal systems for the treatment of diseases such as bronchitis, diabetes, fever, hypertension and several types of inflammation. This review is a critical evaluation of the published data on the more relevant ethnopharmacological and medicinal uses of Inula spp. and on their metabolites biological activities. This study allows the identification of the ethnopharmacological knowledge of this genus and will provide insight into the emerging pharmacological applications of Inula spp. facilitating the prioritirization of future investigations. The corroboration of the ethnopharmacological applications described in the literature with proved biological activities of Inula spp. secondary metabolites will also be explored. MATERIALS AND METHODS The major scientific databases including ScienceDirect, Medline, Scopus and Web of Science were queried for information on the genus Inula using various keyword combinations, more than 180 papers and patents related to the genus Inula were consulted. The International Plant Name Index was also used to confirm the species names. RESULTS Although the benefits of Inula spp. are known for centuries, there are insufficient scientific studies to certify it. Most of the patents are registered by Chinese researchers, proving the traditional use of these plants in their country. Although a total of sixteen Inula species were reported in the literature to have ethnopharmacological applications, the species Inula cappa (Buch.-Ham. ex D.Don) DC., Inula racemosa Hook.f., Inula viscosa (L.) Aiton [actually the accepted name is Dittrichia viscosa (L.) Greuter], Inula helenium, Inula britannica L. and Inula japonica Thunb. are the most frequently cited ones since their ethnopharmacological applications are vast. They are used to treat a large spectrum of disorders, mainly respiratory, digestive, inflammatory, dermatological, cancer and microbial diseases. Fifteen Inula spp. crude extracts were investigated and showed interesting biological activities. From these, only 7 involved extracts of the reported spp. used in traditional medicine and 6 of these were studied to isolate the bioactive compounds. Furthermore, 90 bioactive compounds were isolated from 16 Inula spp. The characteristic compounds of the genus, sesquiterpene lactones, are involved in a network of biological effects, and in consequence, the majority of the experimental studies are focused on these products, especially on their cytotoxic and anti-inflammatory activities. The review shows the chemical composition of the genus Inula and presents the pharmacological effects proved by in vitro and in vivo experiments, namely the cytotoxic, anti-inflammatory (with focus on nitric oxide, arachidonic acid and NF-κB pathways), antimicrobial, antidiabetic and insecticidal activities. CONCLUSIONS Although there are ca. 100 species in the genus Inula, only a few species have been investigated so far. Eight of the sixteen Inula spp. with ethnopharmacological application had been subjected to biological evaluations and/or phytochemical studies. Despite Inula royleana DC. and Inula obtusifolia A. Kerner are being used in traditional medicine, as far as we are aware, these species were not subjected to phytochemical or pharmacological studies. The biological activities exhibited by the compounds isolated from Inula spp., mainly anti-inflammatory and cytotoxic, support some of the described ethnopharmacological applications. Sesquiterpene lactone derivatives were identified as the most studied class, being britannilactone derivatives the most active ones and present high potential as anti-inflammatory drugs, although, their pharmacological effects, dose-response relationship and toxicological investigations to assess potential for acute or chronic adverse effects should be further investigated. The experimental results are promising, but the precise mechanism of action, the compound or extract toxicity, and the dose to be administrated for an optimal effect need to be investigated. Also human trials (some preclinical studies proved to be remarkable) should be further investigated. The genus Inula comprises species useful not only in medicine but also in other domains which makes it a high value-added plant.

2-Styrylchromones As Novel Inhibitors of Xanthine Oxidase. A Structure-activity Study

The purpose of this study was the evaluation of the xanthine oxidase (XO) inhibition produced by some synthetic 2-styrylchromones. Ten polyhydroxylated derivatives with several substitution patterns were synthesised, and these and a positive control, allopurinol, were tested for their effects on XO activity by measuring the formation of uric acid from xanthine. The synthesised 2-styrylchromones inhibited xanthine oxidase in a concentration-dependent and non-competitive manner. Some IC 50 values found were as low as 0.55 μM, which, by comparison with the IC 50 found for allopurinol (5.43 μM), indicates promising new inhibitors. Those 2-styrylchromones found to be potent XO inhibitors should be further evaluated as potential agents for the treatment of pathologies related to the enzymes activity, as is the case of gout, ischaemia/reperfusion damage, hypertension, hepatitis and cancer.

Synthesis and antioxidant properties of new chromone derivatives.

Nowadays, the recognition of the benefits of antioxidants is eliciting an increasingly interest in the search for new molecules with improved activity. The aim of the present work was to search for improved reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavengers by testing new structures of 2-styrylchromones (2-SC) and 3-substituted flavones, which were synthesised by the Baker-Venkataraman approach. The new compounds were also tested for their metal chelating capacity and reducing activity. The obtained results showed that the methylation of hydroxyl groups decreases the scavenging of ROS and RNS by 2-SC. The decrease in the scavenging activities was, generally, more evident when the methylation occurred in B-ring, except for O2*- and (1)O(2). On the other hand, the introduction of a substituent, either hydroxyl or methoxyl, in position 8 was sometimes favourable and others unfavourable to the scavenging activities, depending on the reactive species. In conclusion, the study of the antioxidant properties of the new 2-SC and flavones allowed establishing new structure-activity relationships and brought out, in some cases, pharmacophores with improved activity.

A convenient synthesis of new (E)-5-hydroxy-2-styrylchromones by modifications of the Baker-Venkataraman method

New 5-hydroxy-2-styrylchromones and 3-cinnamoyl-5-hydroxy-2-styrylchromones have been prepared by modifications of the Baker–Venkataraman method. All compounds were fully characterized using several 1D and 2D NMR techniques. The E stereochemistry of the double bonds of all the 5-hydroxy-2-styrylchromones and the conformational features of those substituted in the 2′ and 2″ positions were unambiguously established by NOE experiments.

5-Hydroxy-2-(phenyl or styryl) chromones: One-pot synthesis and C-6, C-8 13C NMR assignments

Abstract A new procedure to synthesise 5-hydroxy derivatives of 2-phenyl- and 2-styrylchromones is reported. The assignments of their C-6 and C-8 atoms, made by proton-coupled 13 C and selective INEPT NMR spectroscopy, show that the literature data for such carbon centres must be interchanged.

Seaweeds as Preventive Agents for Cardiovascular Diseases: From Nutrients to Functional Foods

Being naturally enriched in key nutrients and in various health-promoting compounds, seaweeds represent promising candidates for the design of functional foods. Soluble dietary fibers, peptides, phlorotannins, lipids and minerals are macroalgae’s major compounds that can hold potential in high-value food products derived from macroalgae, including those directed to the cardiovascular-health promotion. This manuscript revises available reported data focusing the role of diet supplementation of macroalgae, or extracts enriched in bioactive compounds from macroalgae origin, in targeting modifiable markers of cardiovascular diseases (CVDs), like dyslipidemia, oxidative stress, vascular inflammation, hypertension, hypercoagulability and activation of the sympathetic and renin-angiotensin systems, among others. At last, the review also describes several products that have been formulated with the use of whole macroalgae or extracts, along with their claimed cardiovascular-associated benefits.

Xanthone and antifungal constituents from Monnina obtusifolia

Three biphenyls and four xanthones have been isolated from the aerial parts of Monnina obtusifolia. The structures were established on the basis of their spectral data and that of some derivatives. The biphenyls have been isolated previously from the same genus. 1,3,6-Trihydroxy-2,5-dimethoxyxanthone is a new natural product, whereas the other xanthones have been described in other species. The antifungal activity of the isolated compounds has been determined.

Structure elucidation of xanthone derivatives: studies of nuclear magnetic resonance spectroscopy.

1H and 13C NMR spectra remain the first tool used by chemists to perform the structure elucidation of their products on a routine basis. It is common to provide NMR data on both proton and carbon spectra based on one-dimensional experiments, but often only proton resonances are assigned. The increasing complexity of natural compounds and their synthetic related derivatives imply the use of some more recent 1D and 2D NMR techniques. The purpose of this review is to describe the main NMR features of the most common and important classes of xanthones and also to discuss the application of several 1D and 2D NMR techniques in the structure elucidation of these compounds. A brief discussion of these NMR techniques from the point of view of structure elucidation of organic compounds will also be considered. The calculated NMR chemical shifts in the structure elucidation of xanthones and the use of NMR to study their mode of action in biological activities will be also described.

Horseradish peroxidase (HRP) as a tool in green chemistry

Horseradish peroxidase (HRP) is a well-known and commercially available enzyme that has been used over the last years in a wide range of applications from which one can emphasize its leading role in organic synthesis with direct influence in the medical field. This review highlights the versatility of this enzyme, pointing out the work developed in biocatalysis research that provide new interesting products supported in green sustainable methodologies. Therefore, the goal is not to deeply explore the issues related to the mechanistic concepts of the reactions, but to use some selected examples to show the broad range of compounds that can be obtained in reactions with HRP, evidencing its use mainly in organic synthesis.