Antineoplastic constituents

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... 

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 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-... 

Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner EE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB, Bontems RJ. The isolation and structure of a remarkable marine animal antineoplastic constituent dolastatin 10. J. Am. Chem. Soc. 1987 109 6883-6885. 

Earlier, some of the same considerations had led me in 1957 to initiate a study of amphibian venoms of the steroidal bufadienolide (6) type as potential sources of new antineoplastic substances. Eventually we found that some of the toad venom bufadienolides such as marinobufagin significantly inhibit growth of the National Cancer Institute s KB cell line derived from a human nasopharynx carcinoma and lead to a curative response with the murine Ehrlich ascites system (7). However, the therapeutic indices were unattractive for further development. So the effort was extended in 1965-66, as Just noted, to encompass a geographically far-reaching area (Asia, Africa, Australia etc.) and an extensive research program to evaluate marine invertebrates and arthropods for structurally unique and useful anticancer constituents. Subsequently we isolated the first such invertebrate antineoplastic constituents (8-12). Meanwhile, our early expectations have been abundantly realized and the discovery of the bryostatins provides a splendid illustration. 

As emphasized above in the summary of A. convoluta research, B. neritina contains very potent antineoplastic constituents with the capacity to intrude upon or otherwise become associated with certain other marine organisms. Therefore, the possibility of Bugula contamination should be considered prior to selecting a new marine animal for detailed chemical study directed at isolation of possible antineoplastic constituents. 

As screening capacity in the U.S. National Cancer Institute s P388 lymphocytic leukemia (PS) test increased in the 1965-1968 period it began to have a very beneficial impact on the success of our research directed at the discovery of marine animal antineoplastic constituents. The early (6) and more recent 13) evolutionary direction of the NCI antineoplastic and cytostatic evaluation systems has been reviewed. By 1968 extracts of B. neritina reached the confirmed active level and consistently allowed over a 100% increase in life span. Bioassay guided isolation was begun with the PS in vivo system and supplemented from 1975 on with the PS in vitro cell line. The in vivo and in vitro activity... 

Pettit, G.R., Y. Kamano, C.L. Herald, and M. Tozawa Structure of Bryostatin 4. An Important Antineoplastic Constituent of Geographically Diverse Bugula neritina (Bryozoa). J. Amer. Chem. Soc. 106, 6768 (1984). 

Pettit, G.R., Kamano, Y, Herald, C.L., and Tozawa, M. (1984) Structure of bryostatin 4 an important antineoplastic constituent of geographically diverse Bugula neritina (bryozoa)./. Am. Chem. Soc.. 106, 6768-6771. 

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