Dolastatins

In contrast, jasplakinolide, a cyclodepsipeptide from the marine sponge Jaspis johnstoni, rapidly penetrates the cell membrane. It competes with phalloidin for F-actin binding and has a dissociation constant of approximately 15 nM. It induces actin polymerization and stabilizes pre-existing actin filaments. Dolastatin 11, a depsipeptide from the mollusk Dolabella auricu-laria, induces F-actin polymerization. Its binding site differs from that of phalloidin or jasplakinolide. 

A similar method was later used by the group of Tomioka [10] for the asymmetric addition of thiazolylhthium 44 to prochiral aldimines (Scheme 10) for the preparation of (S)-Boc-Doe 46, a component of antileukemic marine natural product dolastatin 10. In this case, sparteine 1 was... 

Pavia H, Cervin G, Lindgren A, Aberg P (1997) Effects of UV-B radiation and simulated herbivory on phlorotannins in the brown alga Ascophyllum nodosum. Mar Ecol Prog Ser 157 139-146 Pawlik JR (1993) Marine invertebrate chemical defenses. Chem Rev 93 1911-1922 Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB, Bontems RJ (1987) The isolation and structure of a remarkable marine animal antineoplastic constituent dolastatin 10. J Am Chem Soc 109 6883-6885 Pfander H, Stoll H (1991) Terpenoid glycosides. Nat Prod Rep 8 69-95... 

Aherne GW, Hardcastle A, Valenti M, Bryant A, Rogers P, Pettit GR, Srirangam JK, Kelland LR (1996) Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay. Cancer Chemother Pharmacol 38 225-232 Ahmad S, Pardini S (1990) Antioxidant defense of the cabbage looper, Trichoplusia ni enzymatic responses to the superoxide-generating flavonoid, quercetin and photodynamic furanocou-marin, xantotoxin. Photochem Photobiol 51 305-312 Amsler CD, Fairhead VA (2006) Defensive and sensory chemical ecology of brown algae. Adv BotRes 43 1-91... 

Dolastatin 15 (213) Depsipeptide Tasidotin (Synthadotin, ILX-651) (214) Oncology Induces G2/M phase cell cycle arrest by inhibiting tubulin assembly Phase II Genzyme 952-954... 

Dolastatin 10 (215) Depsipeptide Soblidotin (YHI-501, TZT-1027, Auristatin PE) (216) Oncology Tubulin assembly inhibition Phase II Yakult Honsha (ASKA Pharmaceutical) 955... 

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. 

Mita AC, Hammond LA, Bonate PL, Weiss G McCreery H, Syed S, Garrison M, Chu QS, DeBono JS, Jones CB, Weitman S, Rowinsky EK. (2006) Phase I and pharmacokinetic study of tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors. Clin Cancer Res 12 5207-5215. 

Scheme 37 Structures of Cyclooxazoline (Westiellamide),1571 5S"1 Ascidialcyclamide,1551-569-5821 and Dolastatine E1564-5811...

Miyazaki, K. Kobayashi, M. Natsume, T. Gondo, M. Mikami, T. et al. (1995) Synthesis and antitumor activity of novel dolastatin 10 analogs. Chem. Pharm. Bull., 43,1706-18. 

Cytotoxic cyclic peptides have also been found in mollusks. Dolastatin peptides are a group of cyclic and linear peptides with prominent cell growth-suppressing activity that were isolated from the marine mollusk... 

D. auricularia is a shell-less mollusk that, therefore, initially appears to lack defenses against predators however, this is only a preliminary supposition. Accumulated evidence supports the fact that Opisthobran-chia mollusks have developed very powerful chemical defenses (Pettit et ah, 1989). Pettit et al. (1981) were the first to isolate some of these compounds the pentapeptide dolastatin 10 (Fig. 5.1) was reported to be the most active natural anticancer substance at that time with an ED50 of 4.6x 10 5pg/mL against the P388 cell line (Pettit et al., 2008). Dolastatin 10 was also shown to inhibit tubulin polymerization and tubulin-dependent GTP hydrolysis (Bai et al., 1990). 

Dolastatin 10 has been evaluated with promising results in a phase I clinical study in patients with solid tumors. Subsequently, its noticeable antitumor activity was well documented in various in vitro and in vivo tumor models (Madden et al., 2000). More than a dozen dolastatin peptides have been isolated to date. Recent studies have shown, for example, that the depsipeptide dolastatin 11 arrests cells at cytokinesis by causing a rapid and massive rearrangement of the cellular actin filament network and induces the hyperpolymerization of purified actin (Bai et al., 2001). The effects of dolastatin 11 were similar to those of the sponge-derived depsipeptide jasplakinolide however, dolastatin 11 exhibited threefold more cytotoxicity than jasplakinolide in the cells studied. 

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

Bai, R., Pettit, G. R., and Hamel, E. (1990). Binding of dolastatin 10 to tubulin at exchangeable nucleotide and Vinca alkaloid sites. J. Biol. Chem. 265,17141-17149. 

Madden, T., Tran, H. T., Beck, D., Huie, R., Newman, R. A., Pusztai, L., Wright, J. J., and Abbruzzese, J. L. (2000). Novel marine-derived anticancer agents A phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors. Clin. Cancer Res. 6,1293-1301. 

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 pentapeptide dolastatin 10 (198) was isolated from D. auricularia and the structure was proposed on the basis of spectral studies [195], Dolastatin 10 (198) is a very potent antineoplastic agent. The absolute configuration proposed from spectral analysis was confirmed by synthesis [196] and dolastatin 10 (198) has subsequently been synthesised by several other research groups [197-199],... 

D. auricularia from Japan contained dolabellin (199), a cytotoxic bis-thiazole. The structure was elucidated by spectral data examination and chemical degradation [200], D. auricularia also contained the cyclic hexapeptide dolastatin E (200) [201], the stereochemistry of which was determined by chemical degradation and total synthesis [202], A further cytotoxic hexapeptide, dolastatin I (201) was isolated from D. auricularia from Japan [203] and the stereostructure was confirmed by enantioselective synthesis [204], Dolastatin 18 (202) was isolated as a very minor cytotoxic component of D. auricularia from Papua New Guinea [205]. 

---