Cytotoxic alkaloids from the flatworm Prostheceraeus villatus and its tunicate prey Clavelina lepadiformis

Kubanek, Julia; Williams, David E.; Silva, E.Dilip de; Allen, Theresa M.; Andersen, Raymond J.

doi:10.1016/0040-4039(95)01246-e

Cited by 98 publications

(104 citation statements)

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“…There are even instances of predators sequestering and using secondary metabolites from ascidians for their own defence: e.g. gastropods (Paul et al 1990) and flatworms (Kubanek et al 1995). For larvae, fishes and cnidarians (zoanthids and corals) are the common predators (Olson & McPherson 1987, Davis & Butler 1989, Svane & Young 1989, Stoner 1990.…”

Section: Introductionmentioning

confidence: 99%

Defence mechanisms of adults and larvae of colonial ascidians: patterns of palatability and toxicity

Tarjuelo¹,

López‐Legentil²,

Codina³

et al. 2002

Mar. Ecol. Prog. Ser.

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We studied the defence patterns of 6 species of colonial ascidians from the Mediterranean Sea. We tested their palatability to common sympatric predators (fishes and crustaceans). The tests were performed separately for the main compartments (zooids and tunic) of the adults and for larvae. For compartments that proved unpalatable, tests were repeated with chemical extracts. We also tested toxicity with the Microtox method. Total energy content, amount of inorganic material and pH were analysed for all compartments. We looked for patterns of defence among species and compartments, and for relationships of adult/larval palatability, of toxicity/palatability, pH/palatability and food quality/palatability. Overall, we found a high variability among species, compartments and predators, but unpalatability was found in all species in at least 1 test. In general, tunic material was the least and zooid material the most palatable. Only 1 of the species studied had an acidic tunic. Toxicity was in general low and not related to palatability, while energy content was positively related to the latter. The larvae of species with low per zooid fecundity and large larvae (Cystodytes dellechiajei, Polysysncraton lacazei, Diplosoma spongiforme and Pseudodistoma crucigaster) were unpalatable to at least 2 of the predators, while larvae of the 2 species with higher fecundity and smaller larvae (Clavelina lepadiformis and Ecteinascidia herdmanni) were the most palatable. There was no relationship between adult and larval palatability. Tests with extracts substantiated a chemical basis for unpalatability in only a few cases, and there was a pattern of increased palatability of tissues with higher energy content and lower amount of structural material. We conclude that the defence strategies of colonial ascidians are highly variable among species (even of the same family), and that unpalatability may be relatively common and provided by either physical or chemical mechanisms, but that allocation to defence varies between compartments and between ontogenetic states (larvae or adult).KEY WORDS: Chemical defence · Toxicity · Palatability · pH · Caloric content · Larval defence · AscidiansResale or republication not permitted without written consent of the publisher

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Section: Introductionmentioning

confidence: 99%

Defence mechanisms of adults and larvae of colonial ascidians: patterns of palatability and toxicity

Tarjuelo¹,

López‐Legentil²,

Codina³

et al. 2002

Mar. Ecol. Prog. Ser.

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“…26) It has been reported that lepadin B elicits cytotoxic effects with IC 50 values of 44 mM for human brest cancer MCF7, 26 mM for glioblastoma U373, and 38 mM for ovarian carcinoma HEY cells. 27) However, these toxic concentrations are 30-to 60-fold higher than the IC 50 values of (Ϫ)-lepadin B for blockade of the nAChRs expressed in oocytes (Table 1). In fact, the blocking effect of (Ϫ)-lepadin B was reversible and reproducible in the same oocytes (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Marine Alkaloids (-)-Pictamine and (-)-Lepadin B Block Neuronal Nicotinic Acetylcholine Receptors

Tsuneki

You

Toyooka

et al. 2005

Biological & Pharmaceutical Bulletin

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Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that mediate and/or modulate synaptic transmission in the nervous system. [1][2][3] In mammalian brain, neuronal nAChR subunits are identified as a2-a7, a9, a10, and b 2-b 4. 4,5) Ligand-binding studies indicate that the most abundant native nAChRs in the central nervous system are a4b 2 heteromeric receptors and a7 homomeric receptors.6) Although nAChRs have been implicated in several neurological disorders including nicotinic addiction, epilepsy, Parkinson's disease and Alzheimer's disease, 7-9) nicotinic ligands and nicotinic-based therapies have only slowly and minimally become available. [10][11][12][13] A variety of alkaloids were isolated from amphibian skins, including indolizidines, quinolizidines, decahydroquinolines and piperidines, some of which have been identified as noncompetitive blockers of nAChRs at neuromuscular junction and in ganglionic PC12 cells 14) and recombinant neuronal nAChRs expressed in Xenopus oocytes.15) To date, a wide range of toxins, including different types of decahydroquinolines and quinolizidines, have been isolated from ascidians (tunicates, subphylum Urochordata, class Ascidiacea) commonly known as sea squirts.16) Nevertheless, none of the ascidian alkaloids has been tested in pharmacological research to develop therapeutically useful nicotinic drugs. Previously, we have redefined the absolute configuration of two ascidian alkaloids by enantioselective total synthesis: (Ϫ)-pictamine, a quinolizidine alkaloid from Clavelina picta, and (Ϫ)-lepadin B, a decahydroquinoline alkaloid from Clavelina lepadiformis. In the present study, we investigated the effects of (Ϫ)-pictamine and (Ϫ)-lepadin B on the major types of nicotinic receptors (a4b 2 and a7) expressed in Xenopus oocytes. MATERIALS AND METHODS MaterialsAll alkaloids used in this study were synthesized and are shown in Fig. 1. The synthesis of (Ϫ)-pictamine and (Ϫ)-lepadin B was performed as reported previously.17,18) The 3-piperidinol alkaloid (+)-prosafrinine, originally isolated from the leaves of Prosopis africana, has also been synthesized as described previously.19) The structures of these alkaloids are identical to those of the natural products. The other reagents were purchased from Sigma (St. Louis, MO, U.S.A.), unless indicated otherwise.Expression in Xenopus Oocytes To assess the nAChR activity, we measured current through the receptor-channel following the techniques described in detail by Tsuneki et al. 15) In brief, oocytes were isolated from Xenopus laevis frogs and were microinjected with 20 ng cDNAs in the nucleus. The mixture of cDNAs of mouse a4 and mouse b 2 subunits was injected in a ratio of 1 : 1, whereas mouse a7 cDNA was injected alone. Oocytes were used in electrophysiological recordings 3 to 8 d after the injection. All experiments were carried out in accordance with guidelines approved by the Toyama Medical and Pharmaceutical Univer- Ascidians (sea squirts) contain a wealth of alkaloids, but their influence o...

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“…The structurally related but biologically different lepadins 1-8 (Fig. 1) are on the other hand marine alkaloids isolated from three distinct ascidians: Clavelina lepadiformis (found in the North Sea), Didemnum, and Aplidium tabascum (both found in the Great Barrier Reef) [2][3][4][5]. The third group consists of more complex polycyclic alkaloids that besides the DHQ ring system, can contain several other heterocyclic ring systems fused into one molecule.…”

Section: In This Review the Marine Derived Decahydroquinoline Alkaloimentioning

confidence: 99%

Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

Pelšs

Koskinen

2013

Chem Heterocycl Comp

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In this review the marine derived decahydroquinoline alkaloid chemistry and biology is described. A proposal is made for the biosynthetic relationships between acyclic and cyclic C-18 amino alcohol natural products.Keywords: amino alcohols, decahydroquinolines, asymmetric synthesis, biosynthesis, total synthesis. Decahydroquinoline (DHQ) alkaloids are unique natural products that can be divided into three distinct sets. The first group (more than 50 members) of these alkaloids are simple 2,5-disubstituted DHQs isolated from dart poison frogs and ants with the parent member being alkaloid cis-195A, also known as pumiliotoxin C [1]. These diverse cis-or trans-fused decahydroquinolines are equipped with various short alkyl and alkenyl side chains. The structurally related but biologically different lepadins 1-8 (Fig. 1) are on the other hand marine alkaloids isolated from three distinct ascidians: Clavelina lepadiformis (found in the North Sea), Didemnum, and Aplidium tabascum (both found in the Great Barrier Reef) [2][3][4][5]. The third group consists of more complex polycyclic alkaloids that besides the DHQ ring system, can contain several other heterocyclic ring systems fused into one molecule. Representative members of this group are gephyrotoxin and Lycopodium alkaloids [6,7]. This review will focus solely on the second group of DHQ alkaloids which, as distinct from the other two groups of DHQ-containing alkaloids, have not been reviewed in full so far [8]. Lepadin alkaloids differ from dendrobatin frog alkaloids in additional oxygenation at position 3, where the substituent may be a hydroxy or acyloxy group, as well as having eight-carbon long side chains of variable oxidation level at position 5 of the DHQ ring. There are three stereochemical groups of lepadins, each derived from distinct tunicate species (Fig. 1). Lepadin F is an exception, being present in both ascidians from the Great Barrier Reef. Lepadins possess some interesting biological activities: lepadins A and B -cytotoxicity against cancer cell lines, lepadins D-F -antiplasmodal and antitrypanosomal activity. Lately, lepadin B together with pictamine was found to block neuronal nicotinic acetylcholine receptors α4β2 and α7. However, the availability of only small quantities of these natural products has precluded further studies on the development into potential leads for nicotinic based therapies [9].

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Cytotoxic alkaloids from the flatworm Prostheceraeus villatus and its tunicate prey Clavelina lepadiformis

Cited by 98 publications

References 2 publications

Defence mechanisms of adults and larvae of colonial ascidians: patterns of palatability and toxicity

Defence mechanisms of adults and larvae of colonial ascidians: patterns of palatability and toxicity

Marine Alkaloids (-)-Pictamine and (-)-Lepadin B Block Neuronal Nicotinic Acetylcholine Receptors

Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

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