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Molecular recognition of peloruside A by microtubules. The C24 primary alcohol is essential for biological activity.

AuthorsPera, Benet ; Razzak, Mina; Trigili, Chiara ; Pineda, Oriol; Canales, Ángeles ; Martínez Buey, Rubén ; Jiménez-Barbero, Jesús ; Northcote, Peter; Paterson, Ian; Barasoain, Isabel ; Díaz, José Fernando
KeywordsAntitumor agents
Antineoplasic agents
Microtubule-stabilizing agents
Structure–activity relationships
Issue Date16-Aug-2010
CitationChemBioChem, 11(12): 1669 – 1678 (2010)
AbstractPeloruside is a microtubule-stabilizing agent that targets the same site as laulimalide. It binds to microtubules with a 1:1 stoichiometry and with a binding affinity in the low-muM range; thereby reducing the number of microtubular protofilaments in the same way as paclitaxel. Although the binding affinity of the compound is comparable to that of the low-affinity stabilizing agent sarcodictyin, peloruside is more active in inducing microtubule assembly and is more cytotoxic to tumor cells; this suggests that the peloruside site is a more effective site for stabilizing microtubules. Acetylation of the C24 hydroxyl group results in inactive compounds. According to molecular modeling, this substitution at the C24 hydroxyl group presumably disrupts the interaction of the side chain with Arg320 in the putative binding site on alpha-tubulin. The binding epitope of peloruside on microtubules has been studied by using NMR spectroscopic techniques, and is compatible with the same binding site.
DescriptionDetailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors at: cbic_201000294_sm_miscellaneous_information.pdf
Publisher version (URL)http://onlinelibrary.wiley.com/doi/10.1002/cbic.201000294/full
Appears in Collections:(CIB) Artículos
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