(+)-Discodermolide: total synthesis, construction of novel analogues, and biological evaluation

Abstract

Natural products have a well-proven track record as cancer chemotherapeutic agents.i Beginning in the late 1960’s with the approval of the Vinca alkaloids vinblastine and vincristine for the treatment of a number of cancers, natural products have emerged both as treatments and as leads for further drug development. Without a doubt, the most important cancer chemotherapeutic agent to arise from a natural source is paclitaxel (Taxol,® Figure 1),ii a complex diterpene originally isolated from the bark of the Pacific yew Taxus brevifolia. Paclitaxel has met with considerable clinical success for ovarian, breast, and lung carcinomas, but the relative paucity of paclitaxel available from the Pacific yew (4000 trees were sacrificed to furnish 360 grams of the drug) nearly prevented the drug from being developed. The supply problem was ameliorated with the discovery that a structurally similar compound, 10-deacetylbaccatin III, could be extracted readily in much larger quantities from the renewable foliage of the European yew Taxus baccata, that, in turn, could be converted chemically to paclitaxel, or to the more potent synthetic congener Taxotere (Figure 1). Figure 1 Natural and non-natural microtubule-stabilizing agents. Paclitaxel comprises the first member of an ever-growing class of natural products that induce the polymerization of the ubiquitous cellular protein tubulin and suppress microtubule dynamics,iia thus preventing effective cell division. The second entry to this class, the epothilones A and B (Figure 1),iii also hold considerable promise as lead anticancer agents in part because, unlike paclitaxel, the epothilones showed efficacy against several multi-drug resistant (MDR) cell lines.iv However, the most interesting compounds to result from the epothilone studies are the structurally related synthetic analogues. For example, Danishefsky and coworkers discovered that 12,13-desoxyepothilone B (Figure 1), a late stage intermediate in the total synthesis of epothilone B, displayed in vivo tumor growth suppression superior to that of the natural product in mice bearing human xenograft tumors.ivc More importantly, 12,13-desoxyepothilone B (now termed epothilone D), exhibited little to no general cytotoxicity, whereas epothilone B often proved fatal to the treated mice. Further optimization ultimately led the Danishefsky team, in collaboration with Kosan Biosciences, to 26-trifluoro-E-9,10-dehydro-12,13-deoxyepothilone B (Fludelone, Figure 1), an orally available agent that led to complete tumor remission in two tumor xenograft models, with no relapse evident even after 200 days!v This synergy between total synthesis and drug optimization is not solely academic; in 2005, a joint Kosan/Roche venture entered epothilone D into Phase II clinical trialsvi for the treatment of breast, lung, and prostate cancer. Earlier this year that trial was halted in order to focus resources on a second, more promising epothilone B congener (9,10-didehydro-12,13-desoxyepothilone B, Figure 1)vi that was recently introduced into Phase II. Elsewhere, Bristol-Myers Squibb Company has completed Phase III clinical trials on Ixabepilone (another epothilone B analogue),vii and in June of 2007 applied for a New Drug Application for the monotherapy treatment of metastatic or locally advanced breast cancer. A third structurally distinct microtubule-stabilizing natural product, (+)-discodermolide (1, Figure 1), was isolated in 1990 by Gunasekera and coworkers at the Harbor Branch Oceanographic Institute from the deep-sea marine sponge Discodermia dissoluta.viii Employing a battery of NMR experiments, including 1H, 13C, COSY, long-range COSY, and several 2D correlation experiments, the Gunasekera team determined that (+)-discodermolide is comprised of a linear polypropionate backbone, punctuated by Z-olefinic linkages at C(8,9) and C(13,14), a terminal Z-diene substituent at C(21–24), thirteen stereogenic centers (including four secondary hydroxyls and seven methyl substituents), a carbamate, and a fully substituted δ-lactone. While the relative stereochemistry was determined by X-ray crystallography, the absolute stereochemistry of (+)-discodermolide remained unknown until 1993, when Schreiber and coworkers reported the first total synthesis in the discodermolide area,ixa which unfortunately proved to be the unnatural antipode. The Schreiber group then prepared the natural congener.ixc (+)-Discodermolide, like the epothilones, retains tumor cell growth inhibitory activity against several MDR cancer cell lines. However, (+)-discodermolide exhibits a number of characteristics unique among the micro-tubule-stabilizing agents, including a linear (not macrocyclic) framework, immunosuppressive properties both in vitroxa and in vivo,xb potent induction of an accelerated senescence phenotype,xi and synergistic antiproliferative activity in combination with paclitaxel.xii Importantly, despite the discovery of several additional microtubule-stabilizing natural products — including eleutherobin,xiii sarcodictyins A and B,xiv laulimalide and isolaulimalide,xv dictyostatin,xvi peloruside A,xvii {type:entrez-nucleotide,attrs:{text:FR182876,term_id:258312082,term_text:FR182876}}FR182876,xviii WS9885B,xix taccalonolides,xx and the coumarinsxxi — discodermolide remains the most potent natural promoter of tubulin assembly yet discovered.xxii The intriguing biological activity profile has prompted a number of efforts directed towards the total synthesis of (+)-discodermolide, as well as towards the production and evaluation of synthetic analogues. The sections to follow present a detailed account of each of these aspects of discodermolide research.