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The structure of euniolide, a new cembranoid diterpene from the Caribbean Gorgonians Eunicea succinea and Eunicea mammosa
Abstract
Three simple γ-lactonic cembranolides were isolated from the gorgonian Eunicea succinea collected near Palomino Key, Puerto Rico on July,1989. The structure of two were determined from spectral data and chemical correlation experiments to be those of known 12,13-bisepleupalmerin (1) and eunicin (3). The structure of the third metabolite was deduced from spectroscopic data and from chemical degradation experiments to be that of eunlolide (2), a previously undescribed γ-lactonic cembranolide. Extraction of a fresh specimen of Eunicea mammosa collected near Desecheo island Puerto Rico on March, 1989 also afforded sunlolide in addition to known cembranoid diterpene eupalmerin acetate (4).
... Five new cytotoxic cembranolides (321-325) possessing a rare 4,7-oxa-bridged functionality were isolated from the gorgonian Eunicea mammosa [100]. Other seven cembranolides including eupalmerin (326) [101], eupalmerone (327), chlorohydrin (328) [62], euniolide (329) [102], 12-epieunicin (330), 4epijeunicin (331), 13-epieupalmerin (332) [103], were also isolated from Eunicea mammosa. The first chemical investigation of the gorgonian octocoral Eunicea pinta, lead to the isolation and structure determination of eight new cembranolides, including 12epieupalmerone (333) and uprolides H-M (334-340). ...
... [45,46,50] Sarcophyton flexuosum 15-17, [11] Sarcophyton stolidotum 372-378 [114] Sarcophyton elegans 18, 19 [12] Sarcophyton cherbonnieri 277, 279, 541 [89] Sarcophyton ehrenbergi 20-23, 204, 205, 263, 542, 543 [13,14] Sarcophyton tortrrosurn 154, 592-594 [58] Sarcophyton tortuosum 585-591 [169,170] Sarcophyton latum 152, 153, 361-371, 607, 608 [57,[111][112][113] Sarcophyton mililatensis 129, 544-546 [49], Sinularia dissecta 482, 618 [146,176] Sinularia maxima Sinularia polydactyla 516-518, 635-637 [156,180,181] Sinularia maxima 478, 479 [144] Sinularia scabra 507-512 [153][154][155] Sarcophyton crassocaule 440, 441 [17,127,128] Sinularia manaarensis 383-391 [117] Sinularia erecta 498, 500, 609, 610 [151,152] Sinularia leptoclados 491-493 [150] Sinularia lochmodes 496-498, 461 [174,189] Sinularia querciformis 432-435 [126] Sinularia polydactyla 290, 291 [88] Sinularia grandilobata 112-116 [41] Sinularia flexibilis 121, 186-195, 392-396, 406-429, 611, 612 [43, 67-70, 118, 121-124, 173] Sinularia gardineri 614 [175] Sinularia granosa 436, 437 [126] Sinularia gibberosa 43-48, 117-120, 122, 217-221, 558 [21,28,42,44,74,75] Sinularia parva 430, 431, 494, 495 [125,150] Sinularia mayi 292-294, 615 [92] Sinularia gyrosaisolated 500-505 [53] Sinularia ovispiculata 56 [26] unidentified soft coral 134-141 [51] Euniceu sp. 52, 58-63, 627-631, 640-644 [24,29,179,184] Eunicea pinta 333-340 [104] Eunicea knighti 163-165 [63] Eunicea mammosa 161, 162, 203, 321-332 [62,[100][101][102][103] Eunicea succinea 158-160, 202, 311-320, 620 [61,98,99] Eunicea tourniforti 36-39 [19] Leptogorgia sp. 482-487, 519 [147,148] Leptogorgia alba 473, 474 [138] Leptogorgia laxa 155, 156 [59] Leptogorgia setacea 475, 476 [142] Lophogorgia peruana 157, 462-471, 526 [60,[137][138][139][140]143] Pseudopterogorgia sp. ...
Cembrane-type diterpenoids are a large and structurally varied group of natural products isolated from both terrestrial and marine organisms. The present paper reviews all the metabolites of cembrane diterpenes, reported up to 2010. The natural products discussed in this review can be divided into several different structural families featuring a variety of ring sizes and oxidation patterns. The currently known biological activities will be presented as well.
... The determination of the configurations of γ-lactone ring fused to 14-membered ring at C-1 and C-14 based on the coupling constant between the lactonic methine protons ( 3 J 1,14 ) is dubious [8]. Notably, all of the cis-fused lactones at C-1 and C-14 of cembranolides from the Caribbean gorgonians Eunicea succinea and Eunicea mammosa for which an X-ray analysis has been performed [23] and all trans-fused lactones of durumolides M–Q (1–5) were confirmed after determination of the ring junction of durumolides A–L and durumhemiketalolides A–C using X-ray data and biogenetic considerations [ in the present study were evaluated in vitro for cytotoxicity against P-388, A-459 and HT-29 cancer cell lines using the MTT assay, and antiviral activity against human cytomegalovirus. Preliminary cytotoxic screening revealed that compound 4 exhibited cytotoxicity against P-388 (mouse lymphocytic leukemia) cell line with an ED 50 of 3.8 μg/mL. ...
Chemical investigations of the Dongsha Atoll soft coral Lobophytum durum resulted in the isolation of five new cembranolides, durumolides M-Q (1-5). The structures of compounds 1-5 were characterized by the interpretation of extensive spectroscopic analysis. Compound 4 exhibited cytotoxicity against P-388 (mouse lymphocytic leukemia) cell line with an ED₅₀ of 3.8 μg/mL. Moreover, compound 5 showed significant antiviral activity against human cytomegalovirus with an IC₅₀ of 5.2 μg/mL.
The structures of (+)-cembrene (1), a macrocyclic diterpene hydrocarbon isolated from pine oleoresins (1, 2), and of the two epimeric cembratrienediols 35 and 36, which were obtained from tobacco (3), were reported in 1962. Since these pioneering studies, the structures of some 300 naturally occurring cembranoids have been resolved. These include both hydrocarbons and oxygen-containing compounds, the latter possessing e.g. epoxy, oxo, hydroxy and lactone functions. Many are polyoxygenated.
Three new cembrane-based diterpenes possessing the rare 3,14-oxa-bridged moiety were isolated from the hexane extract of a southwestern Caribbean gorgonian octocoral, Eunicea pinta, together with seven known cembranoid diterpenes. The structures of pintoxolanes A–C (1–3, resp.), including their relative configurations, were deduced from spectroscopic data and chemical-correlation experiments. Experimental evidence hinting to a plausible biogenesis of the 3,14-oxalane moiety is provided. Preliminary cytotoxicity data for compounds 1–3 toward human cancer cell lines are also provided.
The secondary metabolite composition of the gorgonian octocoral Eunicea pinta from San Andres Island, Colombia, is described for the first time. This investigation has resulted in the isolation of eight now gamma-cembranolide-type diterpenes, namely, compounds 3-10, and a new saponin, 13, possessing a pregnene-derived aglycon. In addition, two previously known alpha-methylene-gamma-lactone cembranolides, euniolide (1) and succinolide (2), were also isolated. Their structures were determined on the basis of the results of spectroscopic analysis, X-ray diffraction analysis, and chemical conversions. The discovery of cembranolides 3-10 has prompted us to conclude that the structures proposed earlier for several uprolide-type cembranolides need revision and that a minor stereochemical correction is also in order for succinolide. Cytotoxicity of compounds 3, 4, and 13 toward various cancer cell lines and results of an anti mycobacterial screening for 2, 4, and 13 also are described.
Thirteen new cembranolide diterpenoids, uprolides 3–15, have been isolated from the Caribbean gorgonian Euniceamammosa collected off the West coast of Puerto Rico. Several known metabolites, such as eupalmerin acetate (1) and eupalmerin (2), were also isolated from the same organism. The structures of the new compounds, which also showed modest in vitro cytotoxic activity, were assigned on the basis of extensive nuclear magnetic resonance analysis, chemical correlation studies, and by comparison with analogous spectral data from known cembranolide diterpenoids. One structure (3) was confirmed by X-ray diffraction analysis. Keywords: uprolides, Euniceamammosa, cytotoxicity, Caribbean, gorgonian.
Eleven cembrane-type diterpenes were isolated from the lipid extract of the Caribbean gorgonian Eunicea mammosa. Of these, four alpha-methylene-gamma-lactone derivatives, 1-4, and one alpha-methylene-delta-lactone, 5, had been previously isolated from various gorgonians. The structures of six new cembrane derivatives, eupalmerone M, pseudoplexauric acid methyl ester [8], (7E,11E)-(1S,3S,4R)-3,4;15,17-diepoxycembra7,11-diene [11], (-)-eunicenone [12), cembranoid chlorohydrin 14, and diketone 15, were determined by means of spectroscopic analyses, and compounds 7 and 8 were chemically correlated with known cembranoid diterpenes eupalmerin [2] and pseudoplexaurol [9], respectively. (-)-Eunicenone [12], a rare cembranoid diterpene having the uncommon 11-cis double bond, was found to be the (-)-antipode of cembrane derivative 13 isolated from a South Pacific soft coral. The structure and stereochemistry of chlorohydrin 14 were established in conjunction with a single crystal X-ray analysis.
A method for the synthesis of derivatives of the lead structures euniolide (1), 12,13-bisepieupalmerin (2), and eupalmerin acetate (3) containing tetrahydrofuran and tetrahydropyran ring systems was developed on the basis of alkali-induced intramolecular oxacyclizations. Representatives of the new analogues were submitted to the in vitro antitumor cell-line-screening program of the National Cancer Institute (NCI). While it was shown that a variety of structural modifications are possible, these transformations led typically to nontoxic synthetic cembranoids.
A large series of analogues of Eunicea cembranolides 1–3 were synthesized with the purpose of evaluating their cytotoxicity against 60 human cancer cell-lines. Most of the analogues were as active as the lead compounds and a few displayed increased cytotoxicity. Their syntheses were based on the specific reactivity and stereochemistry of the epoxide substructure and involved highly regio- and diastereoselective acid-induced chemical transformations.
3,7-Diiodo-4,8-epoxy-euniolide (2) was synthesized from euniolide (1) by the addition reaction of iodine in the presence of triphenylphosphine in CH2Cl2. The absolute structure of 2 was unambiguously determined by a combination of 1H and 13C NMR, HREI mass spectroscopy, and x-ray single crystal analysis as (11E, 1S, 3S, 4R, 7S, 8R, 14S)-3,7-diiodo-4,8-epoxy-cembra-11,15-dien-16,14-olide. X-ray crystallographic data for 2: Orthorhombic P212121 (#19), a = 10.9688(7), b = 11.3909(8), c = 16.885(1) , calcd = 1.795 g cm–3, and for Z = 4.
Five new cytotoxic cembranolides possessing a rare 4,7-oxa-bridged functionality were isolated from the gorgonian Eunicea mammosa. The structures of 5, 7-9, and 10 were deduced from spectroscopic data and by chemical correlation experiments.
As part of a collaborative research effort between the University of the Virgin Islands and Virginia Polytechnic Institute and State University, we carried out the extraction and bioassay of 87 marine organisms in a mechanism-based assay involving genetically altered yeast strains. Of these, nineteen showed differential activity between the mutant and wild-type yeast strains indicating the presence of potential DNA interacting agents. We now report the isolation and characterization of five new diterpenoids, 2-6, together with the previously known diterpenoid 1, from the bioactive extracts of the gorgonian Eunicea tourneforti forma atra. The structures of the isolated compounds were determined by employing a variety of one- and two-dimensional nmr methods.
In our continuing comparative study of the diterpenoid content of the Caribbean gorgonian Eunicea succinea from different locations around Puerto Rico, three new cembranolide diterpenes, named 12,13-bisepieupalmerin acetate [5], 12-epi-eupalmerin acetate [6], and succinolide [7], were isolated from specimens collected off the east coast of Puerto Rico. The structure of each compound was deduced spectroscopically, and those of 5 and 7 were confirmed by chemical correlation with compounds of known structure.
1. Three cyclic diterpenoids isolated from gorgonians of the Eunicea genus and characterized as eupalmerin acetate (EUAC), 12,13-bisepieupalmerin (BEEP), and eunicin (EUNI) were found to be pharmacologically active on the nicotinic acetylcholine receptor (AChR). 2. The receptor from the BC3H-1 muscle cell line was expressed in Xenopus laevis oocytes and studied with a two-electrode voltage clamp apparatus. 3. All three compounds reversibly inhibited ACh-induced currents, with IC50's from 6 to 35 microM. ACh dose-response curves suggested that his inhibition was noncompetitive. The cembranoids also increased the rate of receptor desensitization. 4. Radioligand-binding studies using AChR-rich membranes from Torpedo electric organ indicated that all three cembranoids inhibited high-affinity [3H]phencyclidine binding, with IC50's of 0.8, 11.6, and 63.8 microM for EUNI, EUAC, and BEEP, respectively. The cembranoids at a 100 microM concentration did not inhibit [alpha-125I]bungarotoxin binding to either membrane-bound or solubilized AChR. 5. It is concluded that these compounds act as noncompetitive inhibitors of peripheral AChR.
A recent collection and extraction of the common Caribbean sea whip Eunicea succinea from Puerto Rico has produced four previously undescribed representatives of the cembrane family of diterpenes (2, 3, 4, and 6). A new geranylgeraniol derivative, 8, was also isolated as a minor constituent. The chemical structures of the new compounds were carefully established by spectroscopic and chemical methods in addition to detailed NMR spectral comparisons with known cembranoid models from Eunicea.
A new chemical study of the Caribbean gorgonian Eunicea succinea collected in Puerto Rico afforded seven new cembranolides (1-5, 7, and 8). Excepting 1, the new compounds described here possess an unusual unsaturation at either position C-1, C-6, or C-8, and all but 8 possess the C-12R, C-13S stereochemistry usually ascribed to cembranolides from E. succinea. Their chemical structures were carefully established by a combination of chemical and spectroscopic methods in addition to detailed NMR spectral comparisons with known cembranolide models.
The class of diterpenoids with a 14-carbon cembrane ring, the cembranoids, includes both competitive and noncompetitive inhibitors of the nicotinic acetylcholine receptor (AChR). All 20 coelenterate-derived cembranoids studied in this report inhibited [piperidyl-3,4-3H]-phencyclidine ([3H]-PCP) binding to its high-affinity site on the electric organ AChR, with IC50s ranging from 0.9 microM for methylpseudoplexaurate to 372 microM for lophotoxin. Inhibition was complete with all cembranoids but lophotoxin and most Hill coefficients were close to 1. Methylpseudoplexaurate and [3H]-PCP binding was competitive. Methylpseudoplexaurate and the fourth most potent cembranoid, eunicin, competed with each other for [3H]-PCP displacement, indicating that there exist one or more cembranoid sites on the AChR. Cembranoid affinity for the AChR correlated with hydrophobicity, but was also dependent on other features. Methylpseudoplexaurate and n-octanol also competed with each other for [3H]-PCP displacement, indicating that the cembranoid site is linked to the n-octanol site on the AChR. Unlike lophotoxin, the five cembranoids tested did not inhibit [125I]Tyr54-alpha-bungarotoxin binding to the AChR agonist sites. All seven cembranoids tested on oocyte-expressed electric organ AChR reversibly blocked acetylcholine-induced currents, although the inhibitor concentration curves were shallow and the inhibition was incomplete.
Cembranoids are cyclic diterpenoids found in tobacco and in marine invertebrates. The present study established that tobacco cembranoids inhibit behavioral sensitization to nicotine in rats and block several types of nicotine acetylcholine receptors (AChRs). 1) At the behavioral level, rat locomotor activity induced by nicotine was significantly increased after seven daily nicotine injections. This sensitization to nicotine was blocked by mecamylamine (1 mg/kg) and by the cembranoids eunicin, eupalmerin acetate (EUAC), and (4R)-2,7,11-cembratriene-4-6-diol (4R), each at 6 mg/kg. None of these compounds modified locomotor activity of nonsensitized rats. 2) In cells expressing human AChRs, cembranoids blocked carbamoylcholine-induced (86)Rb(+) flux with IC(50) in the low micromolar range. The cell lines used were the SH-EP1-halpha4beta2 cell line heterologously expressing human alpha4beta2-AChR, the SH-SY5Y neuroblastoma line naturally expressing human ganglionic alpha3beta4-AChR, and the TE671/RD cell line naturally expressing embryonic muscle alpha1beta1gammadelta-AChR. The tobacco cembranoids tested were 4R and its diastereoisomer 4S, and marine cembranoids tested were EUAC and 12,13-bisepieupalmerin. 3) At the molecular level, tobacco (4R and 4S) and marine (EUAC) cembranoids blocked binding of the noncompetitive inhibitor [(3)H]tenocyclidine to AChR from Torpedo californica electric organ. IC(50) values were in the submicromolar to low-micromolar range, with 4R displaying an order of magnitude higher potency than its diastereoisomer, 4S.
Two novel cholic acid derivatives and three known steroids were isolated from an octocoral Eleutherobiasp. from Pohnpei Micronesia along with the known briareins minabein-1 (6), minabein-4 (7), minabein-6 (8), minabein-8 (9), and minabein-9 (10). X-ray crystallographic analysis of the known compound minabein-4 allowed assignment of its correct relative and absolute stereochemistry. Consequently, a different structure proposed for the same compound (named independently as nui-inoalide-D) is incorrect.
The known cembranoid diterpene eunicin (1) was isolated from a new genus of octocoral, Pseudoplexaura, collected in the Caribbean. The complete assignment of the 13C and 1H NMR spectra, including differentiation of pro-R and pro-S hydrogens and elucidation of all J values, was accomplished with the aid of TOCSY, HSQC, and HMBC data, and a consideration of three low-energy conformations using SYBYL.
Four new alpha-methylene-gamma-lactone-bearing cembranoids, 20-acetylsinularolide B (6), presinularolide B (7), 3-dehydroxylpresinularolide B (8), and 3-dehydroxyl-20-acetylpresinularolide B (9), together with five known analogues, sinularolides B-E (1- 4) and 20-acetylsinularolide C (5), were isolated from a South China Sea soft coral Lobophytum crassum. Their structures and relative stereochemistry were established by a combination of detailed spectroscopic data analysis and chemical correlations. The structures of 1- 9 were further confirmed by an X-ray diffraction study on a single crystal of sinularolide B (1). The absolute configurations of sinularolide B (1) and presinularolide B (7) were determined by a novel solid-state CD/TDDFT approach and by a modified Mosher's method, respectively. This study also revealed that the coupling constant between the lactonic methine protons ((3) J 1,2) varies considerably with different functional groups on the cembrane ring and that the determination of the stereochemistry of lactone ring fusion based on this coupling constant is risky. In a bioassay, sinularolides B and C (1 and 2) and new cembranoids 7 and 8 showed in vitro cytotoxicity against the tumor cell lines A-549 and P-388.
Three new cembranolide diterpenes from Lobophytum crassospiculatum are reported. The structure of one of these was deduced from spectroscopic data and chemical degradation, then confirmed as (E,E,E)-6,10,14-trimethyl-3-methylene-trans-3a,4,7,8,11,12,15,15a- octahydrocyclotetradeca[b]furan-2(3H)-one (3), by synthesis from the previously reported (2). The other two diterpenes,(4) and (5), are shown to be the epimeric 15-acetoxyl derivatives of (2).
A specimen of Lobophytum cristigalli collected in Sri Lanka afforded two cembranolide diterpenes (7E,11E,1R,2S,3R,4R,14S)-14-acetoxy-3,4-epoxycembra-7,11,15-trien-17,2-olide (6)* and the corresponding alcohol (7). Their structures were deduced spectroscopically and detailed stereochemistry of (6) was determined by X-ray crystallography.
Two isomeric 7,8-epoxycembra-3,11,15-trien-16,2-olides have been isolated from different species of the soft coral genus Efflatounaria. The structure of each was deduced spectroscopically , and the relative stereochemistry of one was determined by X-ray crystallography. The absolute stereochemistry of each cembranolide was obtained by chemical correlation with known compounds.
Popolohuanone-A ( ) and B ( ) are two new sponge metabolites of composition C42H57NO3. Their structures, which were determined by spectral and chemical correlations, comprise two molecules of a benzenoid moiety each linked to a rearranged drimane sesquiterpene and connected by an amino function.
A new bicyclic diterpenoid, palominol (2), of the dolabellane ring system has been isolated from the Caribbean gorgonians Eunicea calyculata and Eunicea laciniata . The structure of this new compound was assigned on the basis of chemical and spectral studies, particularly heteronuclear chemical shift correlation methods, homonuclear spin decoupling experiments and nuclear Overhauser enhancement difference spectroscopy (NOEDS).
Total assignment of the 13C NMR spectrum of the oxa-bridged cembranoid diterpene eunicin was accomplished through the combined use of methylene carbon chemical shift regularity behavior associated with (E)-isoprene-derived structural fragments, lanthanide induced shifts, and two-dimensional proton-carbon chemical shift correlation NMR spectroscopy.
In a continuing comparative study of the sesquiterpenoid and diterpenoid content of the gorgonian Eunicea succinea from different locations, a new cembranolide, 12,13-bisepieupalmerin (6), was isolated (structure by X-ray analysis) from specimens from St. Croix, U.S.V.I. 12,13-Bisepieupalmerin possesses the correct stereochemistry to be a biosynthetic precursor for the related cembranolides eunicin (1a) and jeunicin (2). The latter compounds were found to occur with 6 in E. succinea from St. Croix. Eunicin and its acetate (1b) were obtained from a South Caicos collection. E. succinea from St. Croix, U.S.V.I. and South Caicos contain complex mixtures of hydrocarbons in which (-)-germacrene-A, (+)-beta-elemene, (+)-beta-epibourbonene, (+)-beta-copaene, and (+)-alpha-muurolene were identified.
- Faulkner