Title: Zaragozic Acids
Additional Names: Squalestatins
Literature 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 Type: Zaragozic Acid A
CAS Registry Number: 142561-96-4
CAS Name: (7S)-2,7-Anhydro-3,4-di-C-carboxy-8,9,10,12,13-pentadeoxy-10-methylene-12-(phenylmethyl)-L-erythro-L-glycero-D-altro-7-trideculo-7,4-furanosonic acid 11-acetate 5-[(2E,4S,6S)-4,6-dimethyl-2-octenoate]
Additional Names: squalestatin 1; squalestatin S1
Molecular Formula: C35H46O14
Molecular Weight: 690.73
Percent Composition: C 60.86%, H 6.71%, O 32.43%
Literature 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. [a]D22 +18.3° (c = 0.60 in CHCl3); [a]D25 +37° (c = 1.29 in methanol). uv max (methanol): 214 nm (log e 4.29); uv max (MeCN): 210 nm (E1%1cm 314).
Optical Rotation: [a]D22 +18.3° (c = 0.60 in CHCl3); [a]D25 +37° (c = 1.29 in methanol)
Absorption maximum: uv max (methanol): 214 nm (log e 4.29); uv max (MeCN): 210 nm (E1%1cm 314)
Derivative Type: Zaragozic Acid B
CAS Registry Number: 146389-61-9
CAS Name: (7S,10x,11x,12x)-2,7-Anhydro-3,4-di-C-carboxy-8,9,10,12,13,14,15-heptadeoxy-10,12-dimethyl-15-phenyl-L-glycero-D-altro-pentadec-14-en-7-ulo-7,4-furanosonic acid 5-[(6E,12E)-6,12-tetradecadienoate]
Molecular Formula: C39H54O13
Molecular Weight: 730.84
Percent Composition: C 64.09%, H 7.45%, O 28.46%
Literature References: Accumulation of farnesol contributing to antifungal activity: J. M. Hornby et al., Antimicrob. Agents Chemother. 47, 2366 (2003).
Properties: [a]D25 +5.9° (c = 0.27 in methanol). uv max (methanol): 205, 251 nm (log e 4.44, 4.32).
Optical Rotation: [a]D25 +5.9° (c = 0.27 in methanol)
Absorption maximum: uv max (methanol): 205, 251 nm (log e 4.44, 4.32)
Derivative Type: Zaragozic Acid C
CAS Registry Number: 146389-62-0
CAS Name: (7S)-2,7-Anhydro-3,4-di-C-carboxy-8,9,10,12,13-pentadeoxy-12-(phenylmethyl)-L-erythro-L-glycero-D-altro-7-trideculo-7,4-furanosonic acid 11-acetate 5-[(4E,6R)-6-methyl-9-phenyl-4-nonenoate]
Molecular Formula: C40H50O14
Molecular Weight: 754.82
Percent Composition: C 63.65%, H 6.68%, O 29.67%
Literature 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).
Properties: White powder. [a]D20 +9.6° (c = 0.29 in ethanol). uv max (ethanol): 209, 259 nm (log e 4.16, 2.81).
Optical Rotation: [a]D20 +9.6° (c = 0.29 in ethanol)
Absorption maximum: uv max (ethanol): 209, 259 nm (log e 4.16, 2.81)
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