Spongian Diterpenes Research Articles

Structural diversity in nudibranch chemistry: elucidation of norditerpenes with a dendrillane scaffold from the Australian nudibranch Goniobranchus coi

In addition to three known compounds (1–3), two new rearranged spongian diterpenes (4 and 5) with perhydroazulene and dioxabicyclooctane ring systems were isolated from the mantle and viscera of the Australian nudibranch Goniobranchus coi. The relative configuration of the major spiroepoxide 4 was explored by comparison with those of m-chloroperbenzoic acid oxidation products derived from dendrillolide A (1). Aldehydes 6 and 7 were identified as the ring-opened artefacts of the spiroepoxides 5 and 4 respectively, and yielded ketone 3 on storage. The relative configurations of lactols 8 and 9, isolated as an inseparable mixture of diastereomers, were deduced by molecular modelling and computational studies. Acetylation of the lactol mixture provided dendrillolide A (1), further confirming the structural assignments of 8 and 9. Dissection of animal tissue established that the norditerpenoid metabolites were present in both mantle and viscera tissues.

New diterpenes from the marine sponge Spongionella sp. overcome drug resistance in prostate cancer by inhibition of P-glycoprotein

Spongian diterpenes are a group of marine natural compounds possessing various biological activities. However, their anticancer activity is still poorly studied and understood. We isolated six spongian diterpenes from the marine sponge Spongionella sp., including one new spongionellol A and five previously known molecules. The structures were elucidated using a detailed analysis MS and NMR spectra as well as by comparison with previously reported data. Two of them, namely, spongionellol A and 15,16-dideoxy-15α,17β-dihydroxy-15,17-oxidospongian-16-carboxylate-15,17-diacetate exhibited high activity and selectivity in human prostate cancer cells, including cells resistant to hormonal therapy and docetaxel. The mechanism of action has been identified as caspase-dependent apoptosis. Remarkably, both compounds were able to suppress expression of androgen receptor (AR) and AR-splice variant 7, as well as AR-dependent signaling. The isolated diterpenes effectively inhibited drug efflux mediated by multidrug-resistance protein 1 (MDR1; p-glycoprotein). Of note, a synergistic effect of the compounds with docetaxel, a substrate of p-glycoprotein, suggests resensitization of p-glycoprotein overexpressing cells to standard chemotherapy. In conclusion, the isolated spongian diterpenes possess high activity and selectivity towards prostate cancer cells combined with the ability to inhibit one of the main drug-resistance mechanism. This makes them promising candidates for combinational anticancer therapy.

Spongenolactones A-C, Bioactive 5,5,6,6,5-Pentacyclic Spongian Diterpenes from the Red Sea Sponge Spongia sp.

Three new 5,5,6,6,5-pentacyclic spongian diterpenes, spongenolactones A–C (1–3), were isolated from a Red Sea sponge Spongia sp. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and the absolute configurations of 1–3 were determined on the basis of comparison of the experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. Compounds 1–3 are the first 5,5,6,6,5-pentacyclic spongian diterpenes bearing an β-hydroxy group at C-1. These metabolites were assayed for their cytotoxic, antibacterial, and anti-inflammatory activities. All three compounds were found to exert inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils. Furthermore, 1 showed a higher activity against the growth of Staphylococcus aureus in comparison to 2.

Total Syntheses of Norrisolide-Type Spongian Diterpenes Cheloviolene C, Seconorrisolide B, and Seconorrisolide C.

The first total syntheses of three unusual norrisolide-type rearranged spongian diterpenes, cheloviolene C, seconorrisolide B, and seconorrisolide C, have been accomplished via a common intermediate through late-stage ring-scissoring. The synthesis features a Wolff ring contraction for the synthesis of the trans-hydrindane system, and a crucial retro Diels-Alder reaction/intramolecular ene cyclization for the rapid stereoselective construction of the furo[2,3-b]furan system, which is commonly seen in rearranged spongian diterpenes.

Total Syntheses of Norrisolide‐Type Spongian Diterpenes Cheloviolene C, Seconorrisolide B, and Seconorrisolide C

AbstractThe first total syntheses of three unusual norrisolide‐type rearranged spongian diterpenes, cheloviolene C, seconorrisolide B, and seconorrisolide C, have been accomplished via a common intermediate through late‐stage ring‐scissoring. The synthesis features a Wolff ring contraction for the synthesis of the trans‐hydrindane system, and a crucial retro Diels–Alder reaction/intramolecular ene cyclization for the rapid stereoselective construction of the furo[2,3‐b]furan system, which is commonly seen in rearranged spongian diterpenes.

Spongian Diterpenoids Derived from the Antarctic Sponge Dendrilla antarctica Are Potent Inhibitors of the Leishmania Parasite.

From the CH2Cl2 extract of the Antarctic sponge Dendrilla antarctica we found spongian diterpenes, including previously reported aplysulphurin (1), tetrahydroaplysulphurin-1 (2), membranolide (3), and darwinolide (4), utilizing a CH2Cl2/MeOH extraction scheme. However, the extracts also yielded diterpenes bearing one or more methyl acetal functionalities (5-9), two of which are previously unreported, while others are revised here. Further investigation of diterpene reactivity led to additional new metabolites (10-12), which identified them as well as the methyl acetals as artifacts from methanolysis of aplysulphurin. The bioactivity of the methanolysis products, membranoids A-H (5-12), as well as natural products 1-4, were assessed for activity against Leishmania donovani-infected J774A.1 macrophages, revealing insights into their structure/activity relationships. Four diterpenes, tetrahydroaplysulphurin-1 (2) as well as membranoids B (6), D (8), and G (11), displayed low micromolar activity against L. donovani with no discernible cytotoxicity against uninfected J774A.1 cells. Leishmaniasis is a neglected tropical disease that affects one million people every year and can be fatal if left untreated.

Spongiains A-C: Three new spongian diterpenes with ring A rearrangement from the marine sponge Spongia sp.

Spongiains A-C (1–3), the first examples of spongian diterpenes bearing a pentacyclic skeleton composed of a fused 5/5/6/6/5 ring system through ring A rearrangement, together with four new spongian diterpenes, spongiains D-G (4–7), were isolated from the marine sponge Spongia sp.. The structures with absolute configurations of these compounds were elucidated by the methods of NMR, X-ray diffraction and quantum chemical approaches. The hypothetical biogenetic pathways as well as cytotoxic activities of 1–7 were also discussed.

Spongian Diterpenes Including One with a Rearranged Skeleton from the Marine Sponge Spongia officinalis

Five new diterpenes, including an unprecedented 5,5,6,6,5-pentacyclic diterpene, sponalactone (1), two new spongian diterpenes, 17- O-acetylepispongiatriol (2) and 17- O-acetylspongiatriol (3), and two new spongian diterpene artifacts, 15α,16α-dimethoxy-15,16-dihydroepispongiatriol (4) and 15α-ethoxyepispongiatriol-16(15 H)-one (5), were isolated from a South China Sea collection of the marine sponge Spongia officinalis, together with three known analogues (6-8). The structures of the new diterpenes were elucidated by extensive spectroscopic analysis. The absolute configurations were established on the basis of ECD data. Compounds 1-5 and 7 exhibited moderate inhibition against LPS-induced NO production in RAW264.7 macrophages with IC50 values of 12-32 μM.

Geographic variation in diterpene-based secondary metabolites and level of defence in an aposematic nudibranch,Goniobranchus splendidus

Nudibranchs are often chemically defended with a variety of secondary metabolites that they obtain from dietary sources or produce de novo. This study details the chemical profile of the nudibranch Goniobranchus splendidus across five sites on the east coast of Australia. This species is especially diverse in secondary metabolites and sequesters a multitude of compounds from a varied sponge diet including spongian diterpenes, rearranged diterpenes and norditerpenes. Goniobranchus splendidus has a colourful body pattern, components of which are used to warn predators of toxins. Therefore, description of metabolite occurrence and quantification within G. splendidus individuals from different regions can help provide a better understanding of how animals obtain chemical defences from their diet and how this influences the evolution of warning signals. We found that populations differed in the abundance, type and richness of secondary metabolites, and that there was high individual variation between specimens from the same population. There was high chemical richness in the mantle rim, which differs from the selective accumulation of compounds in some other nudibranch species. We also found geographic differences in the potency of chemical extracts in model bioassays measuring the anti-feedant effects on Palaemon shrimp and toxicity to brine shrimp. Geographic and individual variation in the richness and abundance of secondary metabolites may have important implications for defence against predation. This study highlights the need to investigate intraspecific variation in secondary metabolites to understand better the nature of complex chemical defences in the marine environment.

Two new spongian diterpene analogues isolated from the marine sponge Acanthodendrilla sp

Two new marine natural compounds, 3β-acetoxy-15-hydroxyspongia-12-en (1) and 3-methylspongia-3,12-dien-16-one (2), were isolated from the marine sponge Acanthodendrilla sp., collected in Pulau-Pulau. Compounds 1 and 2 represent new chemical entities of the known spongian diterpene family. Compound 1 is a new 3-acetoxyspongia and compound 2 presents an unreported rearranged 3-methylspongia-3-en. Their structures, including relative configurations, were fully elucidated based on 1D and 2D NMR analyses, as well as HRESTOFMS experiments. No significant bioactivities were found for these compounds. This work reports two new chemical structures, compounds 1 and 2, together with the first isolation of spongian diterpenes from Acanthodendrilla genus.

Complete assignment of the 1 H NMR data and reassignment of 13 C NMR data of four spongian diterpenes.

Complete assignment of the 1 H NMR data and reassignment of 13 C NMR data of four spongian diterpenes.

Ceylonins G-I: spongian diterpenes from the marine sponge Spongia ceylonensis.

Three new spongian diterpenes, ceylonins G-I (1-3), were isolated from the marine sponge Spongia ceylonensis collected in Indonesia, together with five known spongian diterpenes (4-8). Only 4 inhibited USP7 with an IC50 value of 8.2μM.

Ceylonamides A–F, Nitrogenous Spongian Diterpenes That Inhibit RANKL-Induced Osteoclastogenesis, from the Marine Sponge Spongia ceylonensis

Seven new spongian diterpenes, ceylonamides A-F (1-6) and 15α,16-dimethoxyspongi-13-en-19-oic acid (7), were isolated from the Indonesian marine sponge Spongia ceylonensis along with eight known spongian diterpenes, 8-15. Compounds 1-6 were determined to be nitrogenous spongian diterpenes. The isolated compounds were examined for the inhibition of RANKL-induced osteoclastogenesis in RAW264 macrophages. Ceylonamide A (1) exhibited the most potent inhibitory activity with an IC50 value of 13 μM, followed by ceylonamide B (2) (IC50, 18 μM). An examination of the structure-activity relationships of the isolated compounds revealed that the position of the carbonyl group of the γ-lactam ring and bulkiness of the substituent at its nitrogen atom were important for inhibitory activity.

The Oxeatamides: nitrogenous spongian diterpenes from the New Zealand marine sponge Darwinella oxeata.

As part of our ongoing search for novel and bioactive compounds from New Zealand marine organisms, we investigated the extracts of the sponge Darwinella oxeata. NMR-guided fractionation led to the isolation of nine new nitrogenous spongian diterpenes, oxeatamide A (1), iso-oxeatamide A (2), oxeatamides B-G (3-8), and oxeatamide A 23-methyl ester (9), as well as two known compounds, membranolides C and D (10, 11).

Forming tertiary organolithiums and organocuprates from nitrile precursors and their bimolecular reactions with carbon electrophiles to form quaternary carbon stereocenters.

The stereoselective formation of quaternary carbons is one of the most demanding challenges in organic synthesis.1 An especially direct way to construct such stereocenters would be to combine a prochiral tertiary organometallic and a carbon-centered electrophile (Figure 1A). However, this strategy is not mentioned in the numerous reviews of stereoselective synthesis of chiral quaternary carbons,1 and to our knowledge has never been employed in target-directed organic synthesis. This omission undoubtedly derives from the challenge in generating tertiary organometallic intermediates, particularly those containing three alkyl substituents.[2–4] We were recently drawn to explore this undeveloped approach for forming quaternary carbon stereocenters in the context of fashioning the demanding C8–C14 bond and the C8 quaternary stereocenter of rearranged spongian diterpenes such as aplyviolene (4) and dendrillolide A (5) by the reaction of tertiary organocuprate 1 and cyclopentenone 2. This coupling was anticipated to take place from the convex face of nucleophile 1 and from the face of 2 opposite the branched side chain (Figure 1B).[5]

Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes.

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.

Three New Spongian Diterpenes from the Fijian Marine Sponge Spongia sp

Chemical investigation of the marine sponge Spongia sp., collected from the Fiji Islands resulted in the isolation of three new furanoditerpenoids 1-3, along with the known compounds epispongiatriol (4) and 17,19-dihydroxyspongia-13(16),14-dien-2,3-dione (5) While 1 is a new spongian diterpene with a modified oxidation pattern, compounds 2 and 3 represent two new ring A-contracted spongians, displaying a novel and unprecedented nor-spongian carbon skeleton. Despite their labile nature the structures could be established through a combined strategy including complete analysis of spectroscopic data (NMR, MS), molecular modeling and quantum-mechanical calculations.

Omriolide A and B; Two New Rearranged Spongian Diterpenes from the Marine Sponge Dictyodendrilla aff. retiara.

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Omriolide A and B; two new rearranged spongian diterpenes from the marine sponge Dictyodendrilla aff. retiara

Two new rearranged spongian diterpenes designated omriolide A and B were isolated from the southern Kenyan sponge Dictyodendrilla aff. retiara collected at Wasini Is., Shimoni Channel. Omriolide A possesses an octalin linked to a unique trioxatricyclo[5.2.1.0 4,10]decane ring system, forming a tricyclic ‘cap’. Omriolide B comprised a tricyclo[5.4.0.0 2,4]undecane linked to a dioxabicyclo[3.3.0]octane. The structures of both diterpenes were elucidated by interpretation of MS results and, mainly, 1D and 2D NMR spectra.

Syntheses of Oxygenated Spongiane Diterpenes from Carvone. Synthesis of Dorisenone C.

Abstract The synthesis of dorisenone C, a representative member of the spongiane-type diterpene family, is described. The synthesis follows a B→AB→ABC→ABCD approach and is based on the initial preparation of the previously known hydroxy-aldehyde 14 (AB rings) from R -(−)-carvone, followed by an intramolecular Diels–Alder reaction between an oxygenated diene moiety and an acetylenic dienophile for the construction of the C ring (compound 22 ), and adequate manipulation of the Diels–Alder adduct functionality for completion of the spongiane framework.