Concise Total Synthesis of the Marine Natural Product Ageladine A

Shengule, Sudhir R.; Karuso, Peter

doi:10.1021/ol061584y

Cited by 51 publications

(40 citation statements)

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“…All experiments were carried out one or two days after plating cells in collagen coated dishes (see above). The physiological bath solution for measurement of in-and out-ward currents comprised: 125 mM NaCl, 2.5 mM KCl, 1 mM Ageladine A Ageladine A was synthesised from 2-aminohistamine [16] or obtained from the sponge Agelas wiedenmayeri [14].…”

Section: Ionic Currents In Pc12 Cellsmentioning

confidence: 99%

“…This fluorescence is pH dependent as it is stronger under acidic conditions and barely detectable in alkaline solutions [15]. The synthesis of ageladine A has been described by several groups [16,17,18,19], which provides a ready source of this compound and a viable alternative to isolation from natural sources. As ageladine A is pH sensitive and a useful dye for isolated cells as well as transparent whole animals [15] we postulated that the dye might be useful for staining acidic vesicles inside cells.…”

Section: Introductionmentioning

confidence: 99%

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Tracking of fast moving neuronal vesicles with ageladine A

Bickmeyer¹,

Heisenberg²,

Podbielski³

et al. 2010

Biochemical and Biophysical Research Communications

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Tracking of fast moving neuronal vesicles with ageladine A

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Section: Ionic Currents In Pc12 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tracking of fast moving neuronal vesicles with ageladine A

Bickmeyer¹,

Heisenberg²,

Podbielski³

et al. 2010

Biochemical and Biophysical Research Communications

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“…14) Recently, we also completed the total synthesis of 1 based on the biosynthetic route proposed by Fusetani et al, as shown in Chart 1. 1,15) While our synthetic route is almost the same as that independently reported by Shengule and Karuso,14) it is anticipated to be more efficient and practical when taking into account the reagents and chemical yields for each step. We wish to report here the structure-activity relationships for MMP-12 inhibitory activity performed by using the 37 ageladine A analogs prepared by featuring our synthetic route established for 1.…”

Section: Regular Articlementioning

confidence: 83%

“…As for the 2-position of the pyrrole ring, replacement of the bromine atom with a chlorine atom obviously increased the inhibitory activity (see 11). However, the introduction of other groups such as methyl, and phenyl groups clearly decreased the activity (see [12][13][14]. From these results, it appeared that the bromine or chlorine atom at the 2-position plays an important role in MMP-12 inhibitory activity.…”

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confidence: 99%

Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of Ageladine A Analogs

Ando¹,

Terashima

2011

Chem. Pharm. Bull.

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Regular ArticleAgeladine A (1), which is a pyrrol-2-aminoimidazole alkaloid isolated from the marine sponge Agelas nakamurai by Fusetani and colleagues 3) inhibits various subtypes of matrix metalloproteinases (MMPs) such as MMP-1, 2, 8, 9, 12, and 13. Among these MMPs, MMP-12 is considered to be associated with inflammatory diseases caused by macrophage infiltration such as skin diseases, 4-6) atherosclerosis, 7) aneurysms, 8) and cancers. 9-11) We had been studying the possibility of using MMP-12 inhibitors against inflammatory diseases, but had not been able to find a lead compound. Accordingly, we embarked on evaluating 1 as a new lead compound for novel MMP-12 inhibitors. Three total syntheses of 1 have been reported by Meketa and Weinreb 12,13) and Shengule and Karuso. 14) Recently, we also completed the total synthesis of 1 based on the biosynthetic route proposed by Fusetani et al., as shown in Chart 1. 1,15) While our synthetic route is almost the same as that independently reported by Shengule and Karuso,14) it is anticipated to be more efficient and practical when taking into account the reagents and chemical yields for each step. We wish to report here the structure-activity relationships for MMP-12 inhibitory activity performed by using the 37 ageladine A analogs prepared by featuring our synthetic route established for 1. 15) Results and Discussion MMP-12 Inhibitory Activity of Ageladine A Analogs We first, attempted to clarify the structural features of ageladine A (1) itself required for its MMP-12 inhibitory activity, and synthesized the 8 analogs 2-9. The MMP-12 inhibition assay was performed as per the manufacturer's (BioMol) protocol. The results of the MMP-12 inhibitory activity assay of these analogs are summarized in Table 1. The activity of two debromo-analogs 2 and 3 was found to disappear. The Nmethylpyrrole analog 4 showed no activity at all. In addition, the 4 analogs, 5-8 in which the amino or imino groups of imidazo[4,5-c]pyridine ring system are methylated and the deamino analog 9 showed weak or no activity. From these results, it was supposed that the two bromine atoms and the three NH groups (1-NH, 14-NH, and 15-NH 2 : ageladine A numbering) of 1 play an important role in its MMP-12 inhibitory activity. We paid particular attention to the influence of the bromine atoms, and anticipated that a slight Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of Ageladine A Analogs 1,2)Naoki ANDO* ,a and Shiro TERASHIMA b a Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.; 2399-1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan: and b Sagami Chemical Research Institute; 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan. Received November 16, 2010 accepted February 12, 2011 Synthesis of the 37 ageladine A analogs was accomplished by employing the total synthetic route of natural ageladine A previously explored by us. From the matrix metalloproteinase-12 (MMP-12) inhibitory activity assay carried out using the novel analogs, it appeared evident that t...

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“…In 2006 the total synthesis of ageladine A was completed by the groups of Weinreb and Karuso [2,3] and later optimized [4,5].…”

Section: Introductionmentioning

confidence: 99%

Ageladine A, a pyrrole–imidazole alkaloid from marine sponges, is a pH sensitive membrane permeable dye

Bickmeyer

Grube

Klings

et al. 2008

Biochemical and Biophysical Research Communications

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a b s t r a c tThe alkaloid ageladine A, a pyrrole-imidazole alkaloid isolated from marine Agelas sponges shows fluorescence in the blue-green range during excitation with UV light with the highest absorption at 370 nm. The fluorescence of this alkaloid is pH dependent. Highest fluorescence is observed at pH 4, lowest at pH 9 with the largest fluorescence changes between pH 6 and 7. Ageladine A is brominated, which facilitates membrane permeation and therefore allows for easy staining of living cells and even whole transparent animal staining. To calculate the exact pH in solutions, cells, and tissues, the actual concentration of the alkaloid has to be known. A ratiometric measurement at the commonly used excitation wavelengths at 340/380 nm allows pH measurements in living tissues with an attenuated influence of the ageladine A concentration on calculated values. The fluorescence changes report small intracellular pH changes induced by extracellular acidification and alkalization as well as intracellular alkalization induced by ammonium chloride.Ó 2008 Elsevier Inc. All rights reserved.The pyrrole-imidazole alkaloid ageladine A was first isolated and described by Fujita et al.[1] using bioassay guided fractionation of extracts of the marine sponge Agelas nakamurai.The alkaloid showed biological effects such as the inhibition of matrix metallo-proteinases and the inhibition of cell migration of bovine endothelial cells. In 2006 the total synthesis of ageladine A was completed by the groups of Weinreb and Karuso [2,3] and later optimized [4,5].Brominated pyrrole-imidazole alkaloids are known to be fish feeding deterrent against the reef fish Thalassoma bifasciatum [6,7] and demonstrate antibiotic activity [8] even against pathogens like Helicobacter pylori [9]. Especially, the degree of bromination and the guanidine moieties have shown to be important for the alkaloids efficacy to disturb cellular calcium ion entry via voltage operated channels in neuroendocrine cells [10][11][12], which possess mainly L-and N-type calcium channels common in neuronal cells. During these fluorescence measurements of cellular effects by pyrrole-imidazole alkaloids, ageladine A was noticed to show fluorescence during UV excitation [12], which was also described earlier by Fujita et al. [1]. We demonstrate here other surprising properties of ageladine A such as its sensitivity to pH changes covering a wide range and because of its high membrane permeability an easy whole animal pH sensitive staining. Material and methodsCulture methods. PC12 cells from the DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany) were kept in culture medium containing RPMI 1640, 10% fetal calf serum, 5% horse serum, and 100 U penicillin/streptomycin per milliliter. Cells were cultivated in an incubator at 37°C, 90% humidity and 5% CO 2 with regular medium changes twice a week or when additionally necessary. Cells grew in culture flasks and 1-2 days prior to the experiments were seeded into petri dishes coated with coll...

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Concise Total Synthesis of the Marine Natural Product Ageladine A

Abstract: A total synthesis of ageladine A has been achieved by exploiting a Pictet-Spengler-type condensation between 2-aminohistamine and 4,5-dibromo-2-formylpyrrole as the key step.

Cited by 51 publications

References 6 publications

Tracking of fast moving neuronal vesicles with ageladine A

Tracking of fast moving neuronal vesicles with ageladine A

Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of Ageladine A Analogs

Ageladine A, a pyrrole–imidazole alkaloid from marine sponges, is a pH sensitive membrane permeable dye

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