Community Research and Development Information Service - CORDIS

FP7

UEDIN-DSZ-BIO Result In Brief

Project ID: 301678
Funded under: FP7-PEOPLE
Country: United Kingdom

Synthesis of natural anticancer products

The vast chemical and biological diversity of the marine environment is a largely untapped resource that could be used to develop new anticancer drugs. The disorazoles are a group of marine-derived natural products which display promising anticancer activity.
Synthesis of natural anticancer products
Disorazoles are compounds that inhibit cytoskeletal stabilisation in a variety of transformed cell lines, including multidrug resistant cells. Previous attempts to synthesise disorazole C1 were successful but the process was lengthy and complex and the yield was poor. The EU- funded UEDIN-DSZ-BIO proposal was initiated to optimise the synthetic approach.

The oxazole region of disorazole C1 controls much of its reactivity, but has not been explored in structure-activity relationship studies. The synthetic strategy envisaged for the construction of the 30-membered di-lactone disorazole C1 employed an Evans-Tishchenko reaction followed by an alkyne cross metathesis / ring-closing alkyne metathesis sequence to allow the flexible combination of components in this region.

Researchers developed a new synthetic route to the C(1)-C(9) oxazole fragment of disorazole C1. They started with material from the chiral pool that would allow for rapid exchange of the oxazole portion of the natural product for other heterocycles. Thus, a commercially available mannitol derivative was converted into a key primary tosylate intermediate, which allowed for straightforward heterocycle introduction by SN2 reactions. Key reactions included a highly (E)-selective palladium catalysed hydrostannylation, a Negishi coupling and stepwise construction of the oxazole from serine. The synthetic sequence was 13 steps long, with an overall yield of 5.4% and an average yield per step of 80%.

Such an ambitious reaction sequence required extensive optimisation. Fortunately, as a result of significant progress in the project, the efforts to complete the total synthesis are currently underway.

Related information

Keywords

Disorazole C1, cancer, cytoskeleton, oxazole, natural products
Record Number: 150752 / Last updated on: 2014-11-20
Domain: Biology, Medicine