Diverted total synthesis: preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties.
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.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Kirk
Douglas
D
Fenster
Michaël D B
MD
Aïssa
Christophe
C
De Souza
Dominic
D
Müller
Oliver
O
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000480:Alkynes / Q000737:chemistry; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D053778:Thiazolidines
D000199:Actins; D000480:Alkynes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D013844:Thiazoles; D053778:Thiazolidines; C037068:latrunculin B; C037067:latrunculin A