Mechanism of action of didemnin B, a depsipeptide from the sea

Li, Li H.; Timmins, Laura G.; Wallace, Tanya L.; Krueger, William C.; Prairie, Mark D.; Im, Wha Bin

doi:10.1016/0304-3835(84)90095-8

Cited by 63 publications

(33 citation statements)

References 7 publications

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“…The authors also reported that phosphoinositide metabolism was blocked with the same EC 50 as measured for WRK(1) cell proliferation. This dual effect on WRK(1) cells was in contrast to the earlier suggestion 35 that the antitumor effect was strictly the result of inhibited protein biosynthesis. The hypothesis that blocked phosphoinositide metabolism and inhibited cell proliferation are related is supported by the additional observation that the diastereomeric epi-nordidemnin B or [Norsta 1 , L-Me-Leu 7 ]didemnin B has no effect on either WRK(1) cell proliferation or phosphoinositide metabolism.…”

Section: Antitumor Activitycontrasting

confidence: 80%

“…This observation is consistent with the earlier ®nding by Montgomery group 47 which showed that the proliferative response was especially susceptible to didemnin B treatment immediately after immunologic activation. Similarly, the in vitro effect on L1210 tumor cells was shown by Li et al 35 to be irreversible after 2 hr, suggesting that didemnin B exerted an effect on some early event during the course of proliferation. Alfrey et al 55 pointed out that the in vivo studies by Stevens et al 51 and Yuh et al, 52 which noted high levels of toxicity, used relatively higher daily doses throughout the experiments.…”

Section: ±46mentioning

confidence: 89%

“…This ®nding, which would appear to have signi®cance in establishing dose schedules for eventual clinical trials, was overlooked until it was independently con®rmed in 1998 by Depenbrock et al 17 A 1984 study by Li et al 35 showed that the antitumor effect upon L1210 cells was irreversible after 2 hr of exposure, again implying that a longer interval of exposure might lead to ampli®ed effects in vitro. The authors also showed that the dose-response for inhibition of DIDEMNIN RESEARCH * L1210 cell growth was nearly superimposable upon that for inhibition of protein biosynthesis, leading to speculation that protein biosynthesis inhibition was the basis for the effects of didemnin B.…”

Section: Antitumor Activitymentioning

confidence: 96%

“…In 1984, Li et al 35 examined the biochemical basis for the antiviral and antitumor activities of didemnins. Unlike other depsipeptide antibiotics, didemnins A and B showed no ionophoric activity.…”

Section: B Antiproliferative Activity and Protein Biosynthesis Inhibmentioning

confidence: 99%

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Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

141

109

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The discovery of the didemnin family of marine depsipeptides launched an exciting and intriguing chapter in natural product chemistry. The unusual structure of the didemnin congeners has led to several total syntheses by research groups from around the world. The impressive in vitro and in vivo biological activities of the didemnins resulted in the first human clinical trials in the U.S. of a marine natural product against cancer, and additional clinical trials of a second-generation didemnin, dehydrodidemnin B (aplidine), are underway. As we mark the 20-year anniversary of the discovery of the didemnins, this class of natural products continues to stimulate active research in fields ranging from synthetic and medicinal chemistry to clinical oncology and cell biology. While some progress was made in dissecting the molecular mechanism of action and in establishing structure-activity relationships, there are still more questions than answers. This review covers the recent didemnin literature, highlighting the work directed towards understanding how this group of natural products interact with fundamental processes such as cell proliferation, protein biosynthesis, and apoptosis. The didemnin field illustrates how natural product chemistry may be used as a critical tool for the study of cell biology.

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Section: Antitumor Activitycontrasting

confidence: 80%

Section: ±46mentioning

confidence: 89%

Section: Antitumor Activitymentioning

confidence: 96%

Section: B Antiproliferative Activity and Protein Biosynthesis Inhibmentioning

confidence: 99%

See 2 more Smart Citations

Natural products as probes of cell biology: 20 years of didemnin research

Vera

Joullié

2002

Medicinal Research Reviews

141

109

View full text Add to dashboard Cite

show abstract

“…Preliminary studies on the mechanism of action of these antibiotics showed that didemnin B is an inhibitor of protein synthesis and that it does not bind DNA (7). It was suggested that its biological activity is mediated primarily through its inhibition of protein synthesis and to a lesser extent by its inhibition of DNA synthesis (8). Unlike other polypeptide antibiotics, such as valinomycin and gramicidin, didemnin B (and also A) does not function as an ionophore (8).…”

mentioning

confidence: 99%