Total synthesis and evaluation of the actin-binding properties of microcarpalide and a focused library of analogues.
A comparative investigation shows that hydroxylated 10-membered lactones modeled around the fungal metabolites microcarpalide (1) and pinolidoxin (2) are endowed with selective actin-binding properties. Although less potent than the marine natural product latrunculin A, which represents the standard in the field, nonenolides of this type are significantly less toxic and accommodate substantial structural editing. Most notable is the fact that even an intramolecular transesterification with formation of a hydroxylated butanolide skeleton does not annihilate their microfilament disrupting capacity. This finding calls for a reinvestigation of the biological profile of other fungal metabolites that embody a similar motif. Microcarpalide (1) serving as the calibration point for this comparative study was prepared by total synthesis based on ring-closing metathesis (RCM) as the key step. The chosen route favorably compares to previous approaches to this target and provides further support for the notion that the (E,Z)-configuration of a medium-sized cycloalkene can be controlled by proper choice of the catalyst as previously outlined by our group. 9-epi-Microcarpalide 26 and furanone 27 as representative examples of the "natural productlike" compounds investigated herein have been characterized by crystal structure analysis.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Nagano
Takashi
T
Müller
Christoph
C
Seidel
Günter
G
Müller
Oliver
O
D015107:4-Butyrolactone / Q000494:pharmacology; D000199:Actins / Q000378:metabolism*; D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D005658:Fungi / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism; D053778:Thiazolidines / Q000494:pharmacology
D000199:Actins; D000473:Alkanes; D000475:Alkenes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006573:Heterocyclic Compounds, 1-Ring; D007659:Ketones; D053778:Thiazolidines; C442266:microcarpalide; C410769:pinolidoxin; D015107:4-Butyrolactone; C037067:latrunculin A