Dolabella auricularia

Extract and caulerpenyne from Guam specimens inhibit feeding by the mollusk Dolabella auricularia (Pennings and Paul 1992)... 

Bai R, Friedman SJ, Pettit GR, Hamel E. (1992) Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia. Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol 43 2637-2645. 

Marine organisms represent a largely unexplored source of unique toxic chemicals. These toxins are produced by the organisms as defense weapons against their predators. Several potent compounds demonstrating antitumor activity in vitro and in vivo have been isolated from marine organisms, e. g., the bryostatins (from Bugula neritina), dolastin 10 (from Dolabella auricularia) and halichondrine B (from Halichondria okadat) [61]. 

Dolabella auricularia). Another prominent family of peptides has also been isolated from mollusks these highly compact and stable linear peptides, known as conotoxins, exhibit specific actions on the ion channels and membrane receptors of excitable cells. 

FIGURE 5.1 Structure of dolastatin 10 derived from the sea hare (mollusk) Dolabella auricularia. 

The antineoplastic, cyclic peptide dolastatin 3 (197) was isolated from the sea hare Dolabella auricularia in small quantities [187]. It bears much structural resemblance to the cyclic peptides of tunicates. Synthetic attempts indicated that the original published structure was incorrect [188]. Three reports of research directed towards synthesis of possible components of dolastatin 3 (197) failed to help with the correct structure [189-191]. Reisolation of 197 allowed the determination of the correct sequence of amino acids in this cyclic pentapeptide and the new structure was confirmed by synthesis [192]. Synthesis of dolastatin 3 (197) and the corresponding 12R diastereoisomer permitted study of the solution... 

The macrolide glycosides, aurisides A (17) and B (18), from the Japanese sea hare Dolabella auricularia show cytotoxicity against HeLa S3 cells with IC50 values of 0.17 and 1.2 pg/ml, respectively [35]. 

The bromotriterpene aurilol (19) also was isolated from the sea hare Dolabella auricularia. Aurilol exhibits cytotoxicity against HeLa S3 cells with an IC50 of 4.3 pg/ml [36]. 

Dolabellin (169), a bisthiazole metabolite from the Japanese sea hare Dolabella auricularia containing 7,7-dichloro-octanoic acid, shows cytotoxicity against HeLa S3 cells (IC5o 6.1 pg/ml). The dechloro analogue has only one third of the toxicity [130]. 

The thiazoline and thiazole rings are present in many cyclic peptides isolated from marine organisms. Most of these types of compound have been isolated from tunicates belonging to the Lissoclinum and Didemnum genus, from sponges of the genus Theonella, and from the sea hare mollusc Dolabella auricularia. The isolation of closely related compounds from cyanobacteria pointed out the symbiont origin of these metabolites. 

The sea hare Dolabella auricularia has been the source of the powerful cytotastic and antineoplastic constituents designated as dolastatins [311]. Some of these compounds are thiazole-containing cyclic peptides. They were found in very small quantities in the animal (ca. 1 mg each from 100 Kg), making the isolation and structural elucidation of these peptides exceptionally challenging. A review on the dolastatins, written by G. R. Pettit in 1997, covers the reported literature regarding their isolation, characterization, biological activity, and synthesis [312]. Pettit and coworkers reported the thiazole-containing dolastatins dolastatin 3 (404) [313], 10 (2) [314], and 18 (407) [315]. The most important dolastatin and the most potent antineoplastic and tubulin-inhibitory substance known to date is the unique linear pentapeptide dolastatin 10 (2). 

The sea hare Dolabella auricularia has furnished aurilol (628), which is cytotoxic (728) and for which the structure has now been fully assigned by total synthesis (729). The Indian Ocean red alga Chondria armata, a member of the Laurencia family, contains armatols A-F (629-634) (730). 

Several other, more complex cysteine-derived polychlorinated peptide metabolites are known to arise in marine organisms. Dolabellin (968) was characterized from the Japanese sea hare Dolabella auricularia 1004). The absolute... 

Suenaga K, Shibata T, Takada N, Kigoshi H, Yamada K (1998) Aurilol, a Cytotoxic Bromotriterpene Isolated from the Sea Hare Dolabella auricularia. J Nat Prod 61 515... 

Sone H, Kondo T, Kiryu M, Ishiwata H, Ojika M, Yamada K (1995) Dolabellin, a Cytotoxic Bisthiazole Metabolite from the Sea Hare Dolabella auricularia Structural Determination and Synthesis. J Org Chem 60 4774... 

Pettit GR, Xu J-P, Doubek DL, Chapuis J-C, Schmidt JM (2004) Antineoplastic Agents 510. Isolation and Structure of Dolastatin 19 from the Gulf of California Sea Hare Dolabella auricularia. J Nat Prod 67 1252... 

Paterson I, Findlay AD, Florence GJ (2007) Total Synthesis and Stereochemical Reassignment of (+)-Dolastatin 19, a Cytotoxic Marine Macrolide Isolated from Dolabella auricularia. Tetrahedron 63 5806... 

The sea hare Dolabella auricularia was recorded to exhibit exceptionally potent biological properties, which were known to certain ancient Greeks and Romans. The most important antineoplastic constituent of D. auricularia was dolastatin 10 (362) (283), a linear pentapeptide that was reported to be the most potent antineoplastic substance known to date. The absolute configuration of362 was ascertained by total synthesis (284). Synthetic studies revealed that the initial structure (285) proposed for dolastatin 3 was incorrect (286-291). The structure of dolastatin 3 was reassigned as 363, and its absolute chirality was established by synthesis (292). The minimum energy conformation of 363 in solution was estab-... 

Metabolites from cyanobacteria are generally of amino acid or polyketide origin and frequently show potent biological activity. The series of dolastatin metabolites, exemplified by dolastatin-10 (Structure 2.18), are linear peptides which show potent cytotoxic activity and are of clinical interest as anti-tumour agents. Originally isolated in very low yield from the Indian Ocean sea hare Dolabella auricularia, dolastatins are now known to be cyanobacterial products.43,44 The discovery of a microbial source for these pharmaceutically important compounds will facilitate study of their biosynthesis and could potentially lead to the production of structural analogues by provision of modified biosynthetic precursors to the cultivar. As discussed below and in Section VI, toxic secondary metabolites from cyanobacteria have often been implicated in the chemical defenses of sea hares.45"17... 

Pennings, S. C. and Paul, V. J., Effect of plant toughness, calcification and chemistry on herbivory by Dolabella auricularia, Ecology, 73, 1606, 1992. 

The order Anaspidea (sea hares) has already been discussed in connection with the derivation of metabolites from algae and cyanobacteria upon which these animals feed. There has been some question as to how well defended they are by metabolites in the skin. Part of the answer is that defensive metabolites do occur in the integument. Dolabella auricularia contains cyclopeptides called auripyrones (Figure 3.13.12).156 Dolabrifera dolabrifera and Petalifera petalifera contain the polypropionate dolabriferol (Figure 3.13.7).157... 

Suenaga, K., Kigoshi, H., and Yamada, K., Auripyrones A and B, cytotoxic polypropionates from the sea hare Dolabella auricularia isolation and structures, Tetrahedron Lett., 39, 5151, 1996. 

Mutou, T., Kondo, T., Ojika, M., and Yamada, K., Isolation and stereostructures of dolastatin G and nordolastatin G, cytotoxic 35-membered cyclodepsipeptides from the Japanese sea hare Dolabella auricularia, J. Org. Chem., 61, 6340, 1996. 

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