Final Activity Report Summary - ELEUTHESYNTHESIS (Synthesis of Eleutheside Analogues : Potential Microtubule-Stabilizing Anticancer Drugs)
Since cancer cells divide more frequently than healthy cells, these substances damage tumours where runaway cell division occurs most profoundly. Of course, other rapidly dividing cells, such as blood cells and hair cells can also be attacked, and consequently side effects are experienced by patients taking these drugs. There are other molecules that share the same mechanism of action as Paclitaxel (stabilization of the microtubules, which play a central role in cell division). It is thought that by acting through a common mechanism, these new leads might share the clinical benefits of Paclitaxel, but their distinct structures will endow them with unique and perhaps improved pharmacological profiles in terms of toxicity and susceptibility to resistance: Sarcodictyins A (1a) and B (1b) and Eleutherobin (2) are some of these. Eleutherobin (2) was isolated from the Eleutherobia species of Australian soft coral in 1997: its scarce availability from natural sources makes its total synthesis vital for further biological investigations. Sarcodictyins A and B and Eleutherobin are active against Paclitaxel-resistant tumour cell lines and therefore hold potential as second generation microtubule-stabilizing anticancer agents. To date, Sarcodictyins A and B have been synthesised successfully by Nicolaou et al., who have also exploited a similar route for accessing Eleutherobin. A subsequent report by Danishefsky and co-workers details an elegant alternative access to Eleutherobin.
We have completed the preparation of an advanced intermediate of the synthesis by Danishefsky, thus accomplishing a formal total synthesis of eleutherobin. In addition, the synthesis of a number of novel, simplified, C-7 substituted eleutheside analogues with potent tubulin-assembling and microtubule-stabilizing properties has been completed, using ring closing metathesis as the key-step for obtaining the [8.4.0] fused bicyclic ring system. One of the simplified analogues (7) of the natural product (lacking inter alia the C-4/C-7 ether bridge) retains potent microtubule-stabilizing activity. The mechanism of cell cycle arrest induced by this compound is similar to that obtained with paclitaxel. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumour cell lines, approximately two orders of magnitude less than paclitaxel.