Structure−Activity Relationships of the Didemnins

Abstract

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

Antiangiogenic activity of aplidine, a new agent of marine origin

“…Aplidine inhibits endothelial cell proliferation, with an IC 50 similar to that observed for tumour cells. Other studies reported that concentrations of aplidine that completely inhibited colony formation by cancer cells were almost ineffective on bone marrow and cord blood haematopoietic progenitor cells, nonstimulated lymphocytes and hepatocytes (Sakai et al, 1996;Gomez et al, 2001;Albella et al, 2002;Erba et al, 2003;Gajate et al, 2003). In agreement, we found that the concentrations of aplidine that affected endothelial cell proliferation had no relevant antiproliferative effect on epithelial cells.…”

“…Aplidine, dehydrodidemnin B, is a marine-derived antitumour agent isolated from the Mediterranean tunicate Aplidium albicans (Sakai et al, 1996;da Rocha et al, 2001;Vera and Joullie, 2002). It is a cyclic depsipeptide, structurally related to other naturally occurring didemnins, such as didemnin B.…”

“…The molecular mechanism of action of aplidine still remains to be clarified, as different activities of the compound have been described that might potentially contribute to its antitumour activity (Sakai et al, 1996;Vera and Joullie, 2002). The antiproliferative effect of aplidine on cancer cells has been associated to perturbation in the cell cycle, since aplidine, at low concentrations, induces blockade of the cell cycle at G1 and at G2 (Geldof et al, 1999;Erba et al, 2002).…”

In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells

“…Aplidine is a cyclic depsipeptide (Figure 1) structurally related to other naturally occurring didemnins. In contrast to the present candidate, those compounds are only found in various species of a Caribbean tunicate genus, Trididemnin (Sakai et al, 1996). Aplidine shows potent in vitro activity against human tumour solid cell lines, especially non-small-cell lung and colon tumour cells with IC50 values at 0.18 nM and 0.45 nm respectively (Faircloth et al, 1995;Lobo et al, 1997).…”

Effect of Aplidin in acute lymphoblastic leukaemia cells

“…Recently, a G 2 block was described for Aplidin in human leukaemia Molt-4 cell line (Erba et al, 2002). Inhibition of protein synthesis via GTP-dependent elongation factor 1-alpha in vitro (Crews et al, 1994), DNA and RNA syntheses in different cell lines (Crampton et al, 1984;Sakai et al, 1996) and inhibition of ornithine decarboxylase have been reported for Didemnins as well as for Aplidin (Urdiales et al, 1996;Erba et al, 2002).…”