https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The biochemistry and medical significance of the flavonoids.

2.5. Stabilization of IL Emulsions by Nanoparticles 2623 3. Hydrogenations in ILs 2623 3.1. Hydrogenation on IL-Stabilized Nanoparticles 2623 3.1.1. Hydrogenation of 1,3-Butadiene 2623 3.1.2. Hydrogenation of Alkenes and Arenes 2624 3.1.3. Hydrogenation of Ketones 2624 3.2. Homogeneous Catalytic Hydrogenation in ILs 2624 3.3. Hydrogenation of Functionalized ILs 2625 3.3.1. Selective Hydrogenation of Polymers 2625 3.4. Asymmetric Hydrogenations 2626 3.4.1. Enantioselective Hydrogenation 2626 3.5. Role of the ILs Purity in Hydrogenation Reactions 2628

Catalysis in ionic liquids

Starting from the early 1990’s, the chemistry of polyvalent iodine organic compounds has experienced an explosive development. This surging interest in iodine compounds is mainly due to the very useful oxidizing properties of polyvalent organic iodine reagents, combined with their benign environmental character and commercial availability. Iodine(III) and iodine(V) derivatives are now routinely used in organic synthesis as reagents for various selective oxidative transformations of complex organic molecules. Several areas of hypervalent organoiodine chemistry have recently attracted especially active interest and research activity. These areas, in particular, include the synthetic applications of 2-iodoxybenzoic acid (IBX) and similar oxidizing reagents based on the iodine(V) derivatives, the development and synthetic use of polymer-supported and recyclable polyvalent iodine reagents, the catalytic applications of organoiodine compounds, and structural studies of complexes and supramolecular assemblies of polyvalent iodine compounds.

The chemistry of polyvalent iodine has previously been covered in four books1–4 and several comprehensive review papers.5–17 Numerous reviews on specific classes of polyvalent iodine compounds and their synthetic applications have recently been published.18–61 Most notable are the specialized reviews on [hydroxy(tosyloxy)iodo]benzene,41 the chemistry and synthetic applications of iodonium salts,29,36,38,42,43,46,47,54,55 the chemistry of iodonium ylides,56–58 the chemistry of iminoiodanes,28 hypervalent iodine fluorides,27 electrophilic perfluoroalkylations,44 perfluoroorgano hypervalent iodine compounds,61 the chemistry of benziodoxoles,24,45 polymer-supported hypervalent iodine reagents,30 hypervalent iodine-mediated ring contraction reactions,21 application of hypervalent iodine in the synthesis of heterocycles,25,40 application of hypervalent iodine in the oxidation of phenolic compounds,32,34,50–53,60 oxidation of carbonyl compounds with organohypervalent iodine reagents,37 application of hypervalent iodine in (hetero)biaryl coupling reactions,31 phosphorolytic reactivity of o-iodosylcarboxylates,33 coordination of hypervalent iodine,19 transition metal catalyzed reactions of hypervalent iodine compounds,18 radical reactions of hypervalent iodine,35,39 stereoselective reactions of hypervalent iodine electrophiles,48 catalytic applications of organoiodine compounds,20,49 and synthetic applications of pentavalent iodine reagents.22,23,26,59

The main purpose of the present review is to summarize the data that appeared in the literature following publication of our previous reviews in 1996 and 2002. In addition, a brief introductory discussion of the most important earlier works is provided in each section. The review is organized according to the classes of organic polyvalent iodine compounds with emphasis on their synthetic application. Literature coverage is through July 2008.

Chemistry of Polyvalent Iodine

The marine environment has been explored in the search for new bioactive compounds over the last 50 years, becoming a highly important and rich source of potent molecules and drug leads reported to possess a wide scope of activities. Alkaloids constitute one of the largest classes of natural products and are synthesized by terrestrial and marine organisms on all evolutionary levels. Alkaloids are usually present in an organism as a mixture consisting of several major and a few minor compounds of the same biosynthetic origin and differing only in functional groups. This group of compounds has apparently evolved as a defense mechanism against predators and as a result alkaloids are often highly potent and toxic molecules.1 Marine invertebrates have proven to be an outstanding source of active molecules, one of the most promising being indole alkaloids. Although many of these marine alkaloids closely resemble the endogenous amines (serotonin, dopamine or histamine), their potential affinity to various neurological targets and consequential impact on animal behavior is virtually unexplored.

Indole alkaloids, their activity, synthesis and potential use in medicine have been already reviewed in several articles.2 In this review we provide information on current and potential pharmaceuticals including small molecule natural indole alkaloids, their biological properties, structure-activity relationship studies, and especially their potential for the treatment of neurological disorders.

1.1. The indole moiety in drugs
The indole moiety is present in a number of drugs currently on the market. Most of these belong to triptans which are used mainly in the treatment of migraine headaches (Fig. 1). All members of this group are agonists of migraine associated 5HT1B and 5HT1D serotonin receptors. Sumatriptan (Imitrex) was developed by Glaxo for the treatment of migraines and introduced into the market as the first member of the triptan family.3 Relative to the second generation triptans, sumatriptan has lower oral bioavailability and a shorter half-life. Frovatriptan (FROVA®) was developed by Vernalis for the treatment of menstruation associated headaches. Frovatriptan's affinity for migraine specific serotonin receptors 5HT1B is believed to be the highest among all triptans.4 In addition, frovatriptan binds to 5HT1D and 5HT7 receptor subtypes.5 Zolmitriptan marketed by AstraZeneca is used to treat acute migraine attacks and cluster headaches. GlaxoSmithKline's naratriptan (Amerge) is also used in the treatment of migraines and some of its side effects include dizziness, tiredness, tingling of the hands and feet and dry mouth. All available triptans are well tolerated and effective.6 The highest incidence of central nervous system (CNS) related side effects (dizziness, drowsiness) was reported for zolmitriptan (5 mg), rizatriptan (10 mg) and eletriptan (40 mg, 80 mg).7 The differences in side-effect profiles for triptans are not likely caused by their different affinity towards serotonin receptors or other neurological receptors in the CNS. There is a positive correlation between the lipophilicity coefficient and CNS side effects; these undesired effects are also dose-dependent.



Figure 1

Currently available drugs from the triptan group.




1.2. Serotonin receptors – possible targets for neurologically active marine indole alkaloids
Given that depression affects approximately 18 million Americans annually,8 it is crucial to develop new effective treatments for this disorder. Intensive studies are being conducted in the area of new targets for antidepressant drugs,9,10 but most antidepressant drugs still target the neurotransmitter systems, mainly serotonin, dopamine and noradrenaline.

Serotonin is one of the neurotransmitters present in the central and peripheral nervous system which plays an important role in normal brain function and regulates sleep, mood, appetite, sexual function, memory, anxiety and many others.11 Serotonin exerts its effects through seven families of receptors (5-HT1 – 5-HT7) further divided into several subclasses. Except for 5-HT3 receptor which is a ligand-gated ion channel, the serotonin receptors belong to the G-protein coupled receptor family. Due to a lack of selective ligands, there is still little known about several 5-HT receptor subclasses.12 Marine monoindole alkaloids, sharing structure similarities with serotonin, are certain to become useful tools to facilitate the understanding of serotonin receptor function and generate new drug leads for the treatment of depression, anxiety, migraines and other 5HT receptor related disorders.

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Marine indole alkaloids: potential new drug leads for the control of depression and anxiety

Four novel steroidal alkaloids named cortistatins A (1), B (2), C (3), and D (4) consisting of a 9(10−19)-abeo-androstane and isoquinoline skeleton have been isolated from the marine sponge Corticium simplex. The absolute stereostructures of 1−4 were elucidated by detailed 2D NMR, CD, and X-ray crystallographic analyses. Cortistatins A−D inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with high selectivity. Among the four substances, cortistatin A (1) showed the strongest anti-proliferative activity (IC50 = 0.0018 μM) against HUVECs, in which the selective index was more than 3000-fold in comparison with that of normal fibroblast or several tumor cell lines.

Cortistatins A, B, C, and D, Anti-angiogenic Steroidal Alkaloids, from the Marine Sponge Corticium simplex

A new antibiotic indole trimer named trisindoline (1) was isolated, together with a known dioxopiperazine brevianamide F (2), from the culture of a bacterium of Vibrio sp., which was separated from the Okinawan marine sponge Hyrtios altum. The structure of trisindoline (1) has been determined on the bases of physicochemical evidence and chemical synthesis.

Marine natural products. XXXIV. Trisindoline, a new antibiotic indole trimer, produced by a bacterium of Vibrio sp. separated from the marine sponge Hyrtios altum.

Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria.

Altohyrtin A, a potent anti-tumor macrolide from the Okinawan marine sponge Hyrtios altum

The effect of plant glycosides on tumor cell invasion was examined. Among the glycosides tested, ginsenoside Rg3 was found to be a potent inhibitor of invasion by rat ascites hepatoma cells (MM1), B16FE7 melanoma cells, human small cell lung carcinoma (OC10), and human pancreatic adenocarcinoma (PSN-1) cells, when examined in a cell monolayer invasion model. Structurally analogous ginsenosides, Rb2, 20(R)-ginsenoside Rg2 and 20(S)-ginsenoside Rg3 (a stereoisomer of Rg3), showed little inhibitory activity. Neither Rh1, Rh2, 20(R)-ginsenosides Rh1, Rb1, Rc nor Re had any effect. The effective ginsenoside, Rg3, tended to inhibit experimental pulmonary metastasis by highly metastatic mouse melanoma B16FE7 cells as well. Taking account of our previous finding that 1-oleoyl-lysophosphatidic add (LPA) induced invasion by MM1 cells in the monolayer invasion model, the effect of Rg3 on molecular events associated with the invasion induced by LPA was analyzed in order to understand the mechanism of the inhibition. Rg3, which suppressed the invasion induced by LPA, dose-dependently inhibited the LPA-triggered rise of intracellular Ca2+. Protein tyrosine phosphorylation triggered by LPA was not inhibited by Rg3.

Motomasa Kobayashi

Papers

Cortistatins A, B, C, and D, Anti-angiogenic Steroidal Alkaloids, from the Marine Sponge Corticium simplex

Marine natural products. XXXIV. Trisindoline, a new antibiotic indole trimer, produced by a bacterium of Vibrio sp. separated from the marine sponge Hyrtios altum.

Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria.

Altohyrtin A, a potent anti-tumor macrolide from the Okinawan marine sponge Hyrtios altum

Inhibition of in vitro tumor cell invasion by ginsenoside Rg3.