Eudistomin U and Isoeudistomin U, New Alkaloids from the Carribean Ascidian Lissoclinum fragile

Badre, Ayoub; Boulanger, Anna; Abou-Mansour, Eliane; Banaigs, Bernard; Combaut, Georges; Francisco, Christian

doi:10.1021/np50106a016

Cited by 84 publications

(50 citation statements)

References 14 publications

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“…In addition, numerous simple or intricate -carboline alkaloids have been isolated and characterized from various marine invertebrates, which include hydroids [212] (Aglaophenia), bryozoans [174,213,214] (Cribricellina, Catenicella), soft corals [215] (Lignopsis), tunicates [216][217][218][219][220][221][222][223][224][225][226] (Eudistoma, Didemnum, Lissoclinum, Ritterella, Pseudodistoma), and various sponges. Marine ascidians belonging to the genus Eudistoma (family Polycitoridae) are another rich source of biologically active -carboline derivatives.…”

Section: Introductionmentioning

confidence: 99%

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Cao

Peng²,

Wang³

et al. 2007

CMC

616

353

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beta-Carboline alkaloids are a large group of natural and synthetic indole alkaloids with different degrees of aromaticity, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. These compounds are of great interest due to their diverse biological activities. Particularly, these compounds have been shown to intercalate into DNA, to inhibit CDK, Topisomerase, and monoamine oxidase, and to interact with benzodiazepine receptors and 5-hydroxy serotonin receptors. Furthermore, these chemicals also demonstrated a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. In this review, we summerized the biochemical and pharmacological functions of beta-carboline alkaloids.

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Section: Introductionmentioning

confidence: 99%

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

Cao

Peng²,

Wang³

et al. 2007

CMC

616

353

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“…For example, comparison of the biological data of compounds 6 and 19, as well as compounds 16 and 29, revealed that B compounds (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) are not always superior to A compounds (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Both compounds 29 and 19, which contain a 3,4-dihydro-b-carboline skeleton showed notable difference in activity.…”

Section: Resultsmentioning

confidence: 99%

“…[4][5][6] Particularly interesting targets include such compounds as eudistomins 7,8) and manzamines, 9,10) which were isolated from marine tunicates and sponges, respectively. As a class, the oxathiazepine containing eudistomines exhibited potent inhibitory activity toward DNA virus HSV-1.…”

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confidence: 99%

The Preparation and Evaluation of 1-Substituted 1,2,3,4-Tetrahydro- and 3,4-Dihydro-.BETA.-carboline Derivatives as Potential Antitumor Agents

et al. 2005

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Marine natural products which contain a b-carboline skeleton are widely distributed in marine invertebrates. 1-3)The discovery of natural b-carboline metabolites as potent antitumor and antiviral agents has stimulated great interest in the synthetic and pharmacological studies of b-carboline derivatives. [4][5][6] Particularly interesting targets include such compounds as eudistomins 7,8) and manzamines, 9,10) which were isolated from marine tunicates and sponges, respectively. As a class, the oxathiazepine containing eudistomines exhibited potent inhibitory activity toward DNA virus HSV-1. In addition, the antiviral eudistomines C (1) and E (2) were also found active against HSV-2, the Vaccinia virus and RNA viruses.11) The novel structures of manzamines, however, were reported to possess potent antitumor, 12,13) antibacterial, antifungal, and anti-HIV activities.14) The most active was manzamine A (3), a principal metabolite from several species of sponges, which showed cytotoxicity against murine P-388 cells at 0.07 mg/ml. 15) Our previous report has revealed that manzamine A-D and H exhibited potent cytotoxicities against human KB-16, A-549 and HT-29 tumor cell lines. 16)The common b-carboline or 1,2,3,4-tetrahydro-b-carboline moieties appear to be important for the biological activity. In order to investigate the essential structural features for the antitumor activity of manzamine A (3), the synthesis of 1-substituted 1,2,3,4-tetrahydro-and 3,4-dihydro-b-carboline derivatives were initiated. The difficult isolation of manzamine A (3) from sponge and its limited source make this current program more important and significant. A facile synthetic method by the application of Pictet-Spengler reaction [17][18][19][20] and DDQ oxidation 21) allowed the preparation of compounds 4-29. Herein, we wish to report the preparation, characterization and biological evaluation of 1-substituted 1,2,3,4-tetrahydro-and 3,4-dihydro-b-carboline derivatives. Results and DiscussionAs summarized in Chart 1, compounds 4-16 were synthesized from tryptamine (I) and substituted benzaldehydes via Pictet-Spengler cyclization. Subsequent oxidation of 1,2,3,4-tetrahydro-b-carbolines (4-16, A compounds) by DDQ furnished 3,4-dihydro-b-carboline derivatives (17-29, B compounds). The spectral data for 4-29 are illustrated in Experimental. Table 1 shows the biological results for compounds 4-29 and manzamine A (3) as tested against murine P-388 (leukemia) and human tumor cell lines, including KB-16 (nasopharyngeal carcinoma), A-549 (lung adenocarcinoma) and HT-29 (colon adenocarcinoma) in vitro. All of the compounds exhibited promising activity except for 19, which had no activity toward the four tumor cell lines. Among them, compound 29 exhibited the most potent activity against all tested tumor cells. For P-388 inhibitory activity, compounds 8 and 29 were more potent than or comparable to 3. Compounds 4, 12, 14, 15, 25 and 28 showed potent to moderate activity. As for KB-16 cell cytotoxicity, compound 29 was equal in potency to manzamine A ...

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“…Finally, we applied our CH/CH coupling to the synthesis of marine indole alkaloid eudistomin U, 18 which possesses DNA-binding activity (Scheme 3). This short synthesis begins with a MOM protection of commercially available ¢-carboline followed by MTO (methyltrioxorhenium)-catalyzed pyridine oxidation 19 to afford the corresponding N-oxide 4 in 70% yield over two steps.…”

Section: I7kmentioning

confidence: 99%

Oxidative C–H/C–H Coupling of Azine and Indole/Pyrrole Nuclei: Palladium Catalysis and Synthesis of Eudistomin U

et al. 2011

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We have developed a palladium-catalyzed CH/CH coupling reaction of indoles or pyrroles with azine N-oxides. The reaction proceeds selectively at the C3 position of indoles/ pyrroles and the C2 position of azine N-oxides. Furthermore, we have accomplished the synthesis of marine indole alkaloid eudistomin U by utilizing this newly developed CH/CH coupling reaction.Compounds containing indoleazine and pyrroleazine moieties are prevalent in natural products and bioactive molecules (Scheme 1).15 Therefore, the development of efficient methods to construct these frameworks has been a topic of considerable interest in organic chemistry. The fields of biochemistry and medicinal chemistry should also benefit from such a synthetic campaign, since these disciplines may see the use of these coupled heterocycles as lead compounds in drug discovery. Currently, the most reliable synthetic method for making indole/pyrroleazine compounds is by way of palladium-catalyzed cross-coupling reactions of organometallic compounds with haloarenes.2,4,5 However, each coupling partner must be synthesized from its parent heteroaromatic compound, occasionally requiring several steps. Although the direct CH bond arylation of heteroarenes 6,7 has emerged as an attractive methodology that can streamline overall synthesis, successful examples of direct CH bond arylation of electron-deficient nitrogen heterocycles such as azines are rare.7b,8 Herein, we report our finding of palladium-catalyzed indoleazine and pyrroleazine CH/CH coupling reactions. 911First, we examined the CH/CH coupling of an indole derivative and unfunctionalized pyridine. Under palladium catalysis, the coupling product was observed but only in trace amounts. Meanwhile, Fagnou and co-workers reported an indolebenzene CH/CH coupling reaction, 9d,9e and more recently, Chang and co-workers reported the coupling of benzene with pyridine N-oxide. 9g Inspired by these findings, we attempted the coupling of N-protected indole with pyridine N-oxide 12 as a synthon of pyridine. Employing Fagnou's and Chang's reaction conditions, to a 1,4-dioxane solution of Npivaloylindole (1.0 equiv) were added pyridine N-oxide 2a (4.0 equiv), Pd(OAc) 2 (10 mol %), Ag 2 CO 3 (3.0 equiv), and pyridine (1.0 equiv), and the reaction mixture was stirred for 5 h at 105°C to give the desired coupling product in 39% yield. Despite its low yield, this reaction furnished the C3-substituted indole azine coupling product selectively. After extensive screening of conditions including Pd sources, oxidants, additives, solvents, and N-protecting groups on the indole, 13 the yield of the coupling product was increased to 73%, using MOM-protected indole 1a as the substrate, 2,6-lutidine 14 and AgOAc 9c,15 as additives (Table 1, Entry 1).With the optimized conditions for regioselective indole pyridylation in hand, we investigated the scope of direct indole Scheme 1. Natural products containing indoleazine moieties.

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Eudistomin U and Isoeudistomin U, New Alkaloids from the Carribean Ascidian Lissoclinum fragile

Abstract: Chemical investigations of the Caribbean ascidian Lissoclinum fragile (Didemnidae) have resulted in the isolation of new alkaloids which we have designated eudistomin U [1] and isoeudistomin U [2]. Their structures were determined by spectrometric and chemical means.

Cited by 84 publications

References 14 publications

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline Alkaloids: Biochemical and Pharmacological Functions

The Preparation and Evaluation of 1-Substituted 1,2,3,4-Tetrahydro- and 3,4-Dihydro-.BETA.-carboline Derivatives as Potential Antitumor Agents

Oxidative C–H/C–H Coupling of Azine and Indole/Pyrrole Nuclei: Palladium Catalysis and Synthesis of Eudistomin U

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Eudistomin U and Isoeudistomin U, New Alkaloids from the Carribean Ascidian Lissoclinum fragile

Abstract: Chemical investigations of the Caribbean ascidian Lissoclinum fragile (Didemnidae) have resulted in the isolation of new alkaloids which we have designated eudistomin U [1] and isoeudistomin U [2]. Their structures were determined by spectrometric and chemical means.

Cited by 84 publications

References 14 publications

&#946;-Carboline Alkaloids: Biochemical and Pharmacological Functions

&#946;-Carboline Alkaloids: Biochemical and Pharmacological Functions

The Preparation and Evaluation of 1-Substituted 1,2,3,4-Tetrahydro- and 3,4-Dihydro-.BETA.-carboline Derivatives as Potential Antitumor Agents

Oxidative C–H/C–H Coupling of Azine and Indole/Pyrrole Nuclei: Palladium Catalysis and Synthesis of Eudistomin U

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β-Carboline Alkaloids: Biochemical and Pharmacological Functions

β-Carboline Alkaloids: Biochemical and Pharmacological Functions