10114. Zaragozic Acids
Nomenclature
Squalestatins.Description and references
Family of fungal metabolites with a core 4,6,7-trihydroxy-2,8-dioxobicyclo[3.2.1]octane-3,4,5-tricarboxylic acid ring system differing among C6-O-acyl and C1-alkyl side chains. Inhibitors of squalene synthase, which catalyzes the first committed step of the sterol biosynthetic pathway. Originally isolated as zaragozic acid from a fungus found in Jalon River in Zaragosa, Spain and as squalestatins from Phoma sp. C2932 found in a soil sample from Armacao de Pera, Portugal. Isolation and properties of squalestatins 1, 2, and 3: M. J. Dawson et al., J. Antibiot. 45, 639 (1992); structure elucidation: P. J. Sidebottom et al., ibid 648. Isolation, structure, and properties of zaragozic acids A, B, and C: J. D. Bergstrom et al., Proc. Natl. Acad. Sci. USA 90, 80 (1993). Review of discovery and mechanism of action: J. D. Bergstrom et al., Annu. Rev. Microbiol. 49, 607-639 (1995); and antihypercholesterolemia and antifungal properties: N. S. Watson, P. A. Procopiou, Prog. Med. Chem. 33, 331-378 (1996); of chemistry and biology: A. Nadin, K.C. Nicolaou, Angew. Chem. Int. Ed. 35, 1623-1656 (1996); of synthetic studies: A. Armstrong, T. J. Blench, Tetrahedron 58, 9321-9349 (2002).
Derivative
Zaragozic Acid A.Nomenclature
Description and references
Absolute stereochemistry: K. E. Wilson et al., J. Org. Chem. 57, 7151 (1992). Biosynthesis: K. M. Byrne et al., ibid 58, 1019 (1993). Synthesis of bicyclic core: H. Abdel-Rahman et al., J. Chem. Soc. Chem. Commun. 24, 1841 (1993). Total synthesis: K. C. Nicolaou et al., Chem. Eur. J. 1, 467 (1995). Accumulation of farnesol-derived dicarboxylic acids in liver: S. Vaidya et al., Arch. Biochem. Biophys. 355, 84 (1998). Induction of CYP2B enzymes: T. A. Kocarek et al., Mol. Pharmacol. 54, 474 (1998).
Properties
White foam. [α]D22 +18.3° (c = 0.60 in CHCl3); [α]D25 +37° (c = 1.29 in methanol). uv max (methanol): 214 nm (log ε 4.29); uv max (MeCN): 210 nm (E1%1cm 314).Derivative
Zaragozic Acid B.Nomenclature
Description and references
Accumulation of farnesol contributing to antifungal activity: J. M. Hornby et al., Antimicrob. Agents Chemother. 47, 2366 (2003).
Properties
[α]D25 +5.9° (c = 0.27 in methanol). uv max (methanol): 205, 251 nm (log ε 4.44, 4.32).Derivative
Zaragozic Acid C.Nomenclature
Description and references
Isolation and structure elucidation: C. Dufresne et al., Tetrahedron 48, 10221 (1992). Synthesis of bicyclic core: I. Paterson et al., Tetrahedron Lett. 38, 4301 (1997). Total synthesis based on aldol approach: S. Nakamura et al., Tetrahedron 61, 11078 (2005). Review of syntheses: S. Nakamura, Chem. Pharm. Bull. 53, 1-10 (2005).