Dolastatin from Dolabella auricularia

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. 

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... 

Paterson, I., Findlay, A.D., and Florence, G.J. (2007) Total synthesis and stereochemical reassignment of (+)-dolastatin 19, a cytotoxic marine macrohde isolated from Dolabella auricularia. Tetrahedron, 63, 5806-5819. 

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 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). 

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... 

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... 

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. 

Sone, H., Nemoto, T., Ishiwata, H., et al. 1993. Isolation, structure, and synthesis of dolastatin D, a cytotoxic cyclic depsipeptide from the sea gare Dolabella auricularia. Tetrahedron Letters, 34 8449-52. 

Dolastatins are a class of peptides comprised of mostly nonribosomal amino acids. They were isolated from a sea hare Dolabella auricularia (94). Dolastatin-10 (86) is one of the most potent and the best-studied members (95, 96). It exerts it antitumor effect by inhibiting tubulin polymerization and binds at the vinca alkaloid binding site (97, 98). Dolastatin-10 has been studied in Phase II human clinical trials but was discontinued because of lack of efficacy (99). Auristatin PE... 

Several analogues of the dolastatins, potent cytotoxic compounds originally derived from the Indian Ocean seahare, Dolabella auricularia, have now been found in the marine cyanobacteria, Lyngbya majuscula and Symploca hydnoides. These discoveries support the proposal that the dolastatins isolated from D. auricularia are of dietary origin. The implications of such an observation to natural products programmes is discussed. Aspects of the structure elucidation of these complex molecules are also presented. 

The dolastatins are a series of remarkable cytotoxic confounds isolated from the Indian Ocean seahare, Dolabella auricularia Most are peptide derivatives although other Dolabella metabolites are represented in a wide range of biosynthetic chemotypes. The impetus for investigations of D. auricularia as a source of new anticancer compounds derived from the initial discovery in 1972 of potent cytotoxic extracts of this seahare. Many dolastatins with pronounced anticancer activity have now been isolated. The most important of these are dolastatins 10 (1) and 15 (2), the structures of which are shown in Figure 1, analogues of which are in phase I trials as anticancer agents. ... 

However, clinical studies on marine metabolites are often hampered by insufficient supply of material, as it was reported for dolastatin 10 from the sea hare Dolabella auricularia [107]. In the case of manoalide, obtained from the sponge Luffariella variabilis, it remains open whether its use will be restricted to an application in studying inflammatory processes on the cell level or whether it... 

Prominent amongst these marine discoveries are the bryostatins from the marine bryozoan Bugula neritincr, the dolastatins from the shell-less mollusc Dolabella auricularia the cephalostatins from the South African marine worm (a mere 5 mm long) Cephalodiscus gilchristi the sponge... 

Dolastatin 10 (123), a potent antineoplastic and tubulin inhibitory substance, was isolated from an Indian Ocean sea hare Dolabella auricularia. Dolastatin 10 (123) is prepared by the coupling of Dov-Val-dil (121) with Dap-Doe (122) using DEPC in 97% yield.50-52... 

The sea hare Dolabella auricularia (Aplysiidae) has been extensively investigated as a rich source of bioactive natural products, and a number of bioactive peptides and depsipeptides such as dolastatin 10 were isolated from both Western Indian Ocean specimens and Japanese specimens of this animal [for example, 134, 135]. This mollusk was also found to contain macrolide-type natural products. From D. auricularia, collected by hand at a depth of 0-1 m off the coast of the Shima Peninsula, Mie Prefecture, Japan, a 22-membered macrolide, dolabe-lide A (65), was isolated as a cytotoxin with an IC50 value of 6.3 pg/ml against HeLa-S3 cells. The gross structure of 65 was determined by spectroscopic analysis, and its absolute stereochemistry was elucidated by a combination of chemical means and the NMR spectroscopic method [136]. 

The Dolastatins are cytotoxic cyclic pentapeptides isolated from the marine shell-less mollusk Dolabella auricularia [81],... 

Dolastatin 10 is a natural, cytotoxic antimitotic peptide with microtubule-inhibitory and apoptotic effects, isolated from the sea hare Dolabella auricularia. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. " Ratoveloma-nana-Vidal and Genet and co-workers proposed a total synthesis of dolastatin 10, where the three stereogenic centers were created by Ru(II)-catalyzed asymmetric hydrogenations of p-keto esters The reduction of P-keto ester 121 was accomplished with in situ generated [RuBr2(5)-SYNPHOS)] (1 mol%) as a catalyst under 12 bar hydrogen and at 50°C in EtOH. After 24 hours, it was achieved with complete conversion and good diastereoselectivity (3R) (3S) = 98 2. 

Pettit, G.R., Kamano, Y, Herald, C.L., Fujii, Y, Kizu, H., Boyd, M.R., Boettner, F.E., Doubek, D.L., and Schmidt, J.M. (1993a) Antineoplastic agents. Part 247. The dolastatins. Part 18. Isolation and structure of dolastatins 10-15 from the marine mollusc Dolabella auricularia. Tetrahedron, 49, 9151-9170. 

Sone, H., Shibata, T Fujita, T., Ojika, M and Yamada, K. (1996b) Dolastatin H and isodolastatin H, potent cytotoxic peptides from the sea hare Dolabella auricularia isolation, stereostmcture, and synthesis. J. Am. Chem. Soc., 118,1874—1880. 

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