Dolastatin cytotoxic activity

Further examination of cytostatic depsipeptide constituents of the Indian Ocean shell-less mollusc D. auricularia resulted in the isolation of dolastatins 11 (364) (294), 13 (365) together with its dehydro derivative (366) (295), 14 (367) (2%), and 15 (368) (297). Each dolastatin exhibits strong cytotoxic activity against the P388 lymphocytic leukemia cell line, whereas dehydrodolastatin 13 (366) proved to be marginally active. 

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... 

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... 

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. 

Normajusculamide C (369), which is closely related to dolastatin 11 (364), was isolated from a deep-water variety of the blue-green alga Lyngbya majuscula collected at Enewetak Atoll in the Marshall Islands (298). Compound 369 exhibits antimycotic activity. From the same alga L. majuscula were isolated the lipopentapeptides majusculamide D (370) and deoxymajusculamide D (371), with both compounds showing moderate cytotoxicity (299). 

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. ... 

The linear dolastatins (10, 15, and H) are significantly more active than the cyclic forms, but other variables are involved because dolastatin C is only weaHy cytotoxic, with an IC50 of 17pgml . ... 

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