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Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

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Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Kirk,  Douglas
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Fenster,  Michaël D. B.
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Aïssa,  Christophe
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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De Souza,  Dominic
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Citation

Fürstner, A., Kirk, D., Fenster, M. D. B., Aïssa, C., De Souza, D., & Müller, O. (2005). Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties. Proceedings of the National Academy of Sciences of the United States of America, 102(23), 8103-8108. doi:10.1073/pnas.0501441102.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-9661-A
Abstract
Two largely catalysis-based and highly convergent total syntheses of latrunculin A (1) and B (2) were diverted to the preparation of a focused library of analogues of these potent actin-binding macrolides that enjoy widespread use in chemical biology. Because the chosen route allows for structural variations of all characteristic parts of the natural leads, it was possible to map the previously largely unknown structure/activity profile of this class of bioactive natural products. This led to the discovery that the removal of the methyl branches decorating the macrocycle in 2 engenders a significant increase in potency, while streamlining the synthesis to a considerable extent. Moreover, compelling evidence is provided that the conspicuous 2-thiazolidinone ring present in all naturally occurring latrunculins may be an optimal but not an essential structural motif for actin binding because it can be replaced by an oxazolidinone moiety with only slight loss in efficacy. Likewise, the inversion of the absolute configuration of the chiral center at C.16 is well accommodated. From the purely chemical perspective, this investigation attests to the maturity of alkyne metathesis, a method that has received attention as efficient means for the formation of macrocycles only recently.