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.

Many diseases are dominated by persistent growth of capillary blood vessels. Tumor growth is also angiogenesis-dependent. Safe and effective angiogenesis inhibitors are needed to determine whether control of angiogenesis would be therapeutic. Heparin and certain steroids, administered together, can inhibit angiogenesis in a synergistic manner. This "pair" effect suggested that specific hydrophilic cycloamyloses may be suitable heparin substitutes. beta-Cyclodextrin tetradecasulfate administered with a steroid inhibits angiogenesis at 100 to 1000 times the effectiveness of heparin in the chick embryo bioassay. This cyclic oligosaccharide also augments the anti-angiogenic effect of angiostatic steroids against corneal neovascularization in rabbits when beta-cyclodextrin tetradecasulfate and a steroid are inserted into the cornea or applied topically as eyedrops.

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Vinca-domain ligands are compounds that bind to tubulin at its inter-heterodimeric interface and favour heterogeneous protofilament-like assemblies, giving rise to helices and rings. This is the basis for their inhibition of microtubule assembly, for their antimitotic activities and for their use in anticancer chemotherapy. Ustiloxins are vinca-domain ligands with a well established total synthesis. A 2.7 Å resolution structure of ustiloxin D bound to the vinca domain embedded in the complex of two tubulins with the stathmin-like domain of RB3 (T(2)R) has been determined. This finding precisely defines the interactions of ustiloxins with tubulin and, taken together with structures of other vinca-ligand complexes, allows structure-based suggestions to be made for improved activity. These comparisons also provide a rationale for the large-scale polymorphism of the protofilament-like assemblies mediated by vinca-domain ligands based on local differences in their interactions with the two tubulin heterodimers constituting their binding site.