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Introduction: Plitidepsin (Aplidin®) is a second-generation didemnin compound that belongs to drugs derived from natural oceanic products. Areas covered: In this review, the authors present the preclinical and clinical data available on this specific marine drug. In vitro and in vivo experiments showed that plitidepsin was active against many tumor models and was able to induce cell cycle arrest at low doses, apoptosis and also had antiangiogenic properties suggesting that this drug may be active in a broad range of human tumors. Phase I trials showed that the drug could be administrated in short or prolonged infusions, with a safety profile much more acceptable than the parent didemnin B molecule. Dose-limiting toxicities were hepatic (cytolysis) and muscular, but were manageable and reversible. No significant bone marrow toxicity was observed. Clinical activity was observed in many tumor types in Phase I that was not reproducible in a high proportion of cases in Phase II. Expert opinion: In hematology, ...

Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory.

The syntheses of three modified peptide fragments of the cyclodepsipeptide didemnin B are reported. The HIP and isostatine (1st) units of the didemnin B macrocycle were simplified to a Z-alanine residue and the ester linkage (through threonine of the tetrapeptide) was replaced with amide linkages through the amines of glycine, D-alanine and an ethylenediamine linker. The latter permitted the attachment of a N-Me-D-Leu-Pro-Lac moiety to afford analogs 2, 3 and 4 respectively.

Although the deprotection of amides by hydrazinolysis is a well established method in carbohydrate chemistry, this reaction is dependent upon the nearby substituents. In our facile synthesis of intermediate benzyl 2-amino-3-azido-4-O-p-methoxybenzyl-6-O-benzyl-2,3-dideoxy-α-d-glucopyranoside (3), we found that the use of trifluoroacetamides provided a more efficient protection strategy.

Didemnin B,(NSC-325319)(Fig.1), a cyclic depsipeptide isolated from a Caribbean tunicate, has been recently determined to be active against B16 melanoma, both in vitro and in vivo, P388 leukemia in vivo (1,2,3,4), and L1210 in vitro (1,3). This agent also inhibits DNA, RNA and protein synthesis (1,2,5,6,) and possesses antiviral activity (3). Using an in vitro stem cell assay, both Jiang, et a1 (5), and Rossof, et a1 (7), have demonstrated Didemnin B to have significant antitumor activity against several human tumor types, including carcinoma of the kidney, lung, breast, and ovary, mesothelioma, sarcoma, and hairy cell leukemia.