Flexible Total-Synthesis of the Novel Antitumor Agent Laulimalide and of Suitable Derivatives thereof.

Although being surprisingly successful, current cancer chemotherapy is still based on the administration of highly toxic drugs, which are not totally selective for cancerous cells. This causes toxic side-effects that limit the effectiveness of almost all the agents in clinical use. Moreover, cancer cells develop multidrug resistance (MDR) to many chemotherapeutic drugs. Among the most promising newly established drugs, paclitaxel (TaxolR) and docetaxel (Taxotere R) have the broadest antitumour spectra in the clinic and are used increasingly for the treatment of ovarian cancer and metastatic breast cancer, with promise also for the treatment of lung, skin, and head and neck cancers. However, this beneficial effect still remains hampered by many drawbacks. Hypersensitivity, neurotoxicity, haematological toxicity and adverse cardiac effects, together with MDR, are limiting factors for the clinical usefulness of the taxane class of anticancer drugs. The major cellular target for paclitaxel and other taxanes is the protein tubulin, whose polymerization into microtubules is induced and stabilized, blocking the tumour cells in mitosis and preventing proliferation. Recently, laulimalide, a metabolite from a pacific marine sponge, has been identified as a novel anticancer drug that exerts potent cytotoxic activity through a paclitaxel-related mechanism and is not liable to MDR. The quantities of laulimalide which are available from the natural source are far too low for any clinical application so that the total synthesis of the compound is clearly indicated. We have projected different synthetic approaches starting from readily available starting materials and promising reasonable yields and high diastereomeric and enantiomeric purity. Additionally, the synthesis is flexible enough to allow the preparation of a variety of derivatives. The synthetic compounds will be tested in vitro with tumor cell lines and in vivo with mice to compare its anticancer qualities to those of paclitaxel, discodermolide, sarcodictyne, eleutherobine and the epothilones.