Pentapeptide dolastatin

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). 

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],... 

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 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 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-... 

Coupling of TV-protected amine 124 and thiazole carboxylic acid (125) is accomplished using the coupling agent DEPC to provide intermediate 126, which is further cyclized to give dolastatin 3 (127), a unique cyclic pentapeptide containing three common amino acids, Pro, Leu, and Val, and two unusual heterocyclic amino acids, the achiral (Gly)Thz and the chiral (GIn)Thz53... 

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

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