Document Type
Article
Abstract
Marine macrolides that selectively disrupt cell cycle events continue to occupy a central position as lead compounds in the ongoing search for novel anticancer agents, [1, 2] highlighted by the recent FDA approval of Halaven (eribulin mesylate, a fully synthetic analogue of the halichondrins) for the treatment of advanced breast cancer.[3] Lithistid sponges have proven to be a particularly fertile source[4] of such biologically relevant polyketide metabolites, including dictyostatin [5] and discodermolide. [5d, 6] As part of a continued program aimed at the discovery of novel bioactive natural products from deepwater marine invertebrates, we have examined the relatively Unexplored [7] lithistid sponge Leiodermatium. A crude extract of Leiodermatium sp. was found to exhibit substantial activity in an assay which identifies antimitotic agents through detection of phosphonucleolin, a marker of mitosis.[8] Bioassay- guided fractionation led to the isolation of leiodermatolide (1, Figure 1), whose unprecedented 16-membered macrolide skeleton, featuring an unsaturated side chain terminating in a d-lactone, has been elucidated through a combination of extensive NMR spectroscopic analysis, comparative DFT GIAO NMR shift calculations, and molecular modeling. Leiodermatolide was found to exhibit potent and selective antimitotic activity (IC50< 10 nm) against a range of human cancer cell lines by inducing G2/M cell cycle arrest, and represents a promising new lead for anticancer drug discovery.
DOI
10.1002/anie.201007719 (doi)
Publication Date
2011
Recommended Citation
This manuscript is an author version with the final publication available at http://onlinelibrary.wiley.com/ and may be cited as: Paterson, I., Dalby, S. M., Roberts, J. C., Naylor, G. J., Guzmán, E. A., Isbrucker, R., Pitts, T. P., Linley, P., Divlianska, D., Reed, J. K., & Wright, A. E. (2011). Leiodermatolide, a potent antimitotic macrolide from the marine sponge Leiodermatium sp. Angewandte Chemie International Edition, 50(14), 3219-3223. doi: 10.1002/anie.201007719
Comments
Florida Atlantic University. Harbor Branch Oceanographic Institute contribution 1825.