✍ Scribed by C.H. Kuo; S.P. Plevyak; T. Biftu; W.H. Parsons; G.D. Berger
No coin nor oath required. For personal study only.
The title compound and its Cdpivaloyloxy methyl (PGM) ester have been synthesized by converting zaragozic acid A to the key intermediate of the protected C3-hydroxymethyl compound 6. Subsequent radical deoxygcnation via the Barton-McCombie procedure. followed by dqnvtection, affarded the product 11 (L-703.370). This compound possesses squalene biosynthesis inhibitory potency of 22% at 24 mpk and its C4-KIM ester, 12 (L-735.142). exhibits an EDso of 1.6 mpk in our oral mouse assay. Zaragozic acid A, t a potent competitive inhibitor of rat liver squalene synthasc with an apparent Ki value of 78 pM. has atly been isolated as one of a family of naturally-occurring fungal metabolitcs.1 The structure of 1 has been determined as a 2,8dioxobicyclo [3.2. l] octane-4,6,7-tiydroxy-3.4,s tricarboxylic acid* In a broader program directed toward chemical modification of this novel molecule to f& analogs with enhanced potency and improved oral absorption, among the many pharmaceutically intczesting compounds.3 the C3-methyl, C3-decarboxy-zaragobc acid A, fi (L703,370.22% inhibition of squalene biosynthesis at 24 mpk in our oral mouse az&ay )p and its pivaloyloxy methyl (POM) ester at C4, u(L-735,142, EDp1.6 mpk oral mouse), have been synthesizcd~ as illustrated below.
📜 SIMILAR VOLUMES
The zaragozic acids and squalestatins, a novel family of fungal metabolites isolated and characterized by researchers at Merck [1] and Glaxo, [2] respectively, in 1992, are the most potent inhibitors of squalene synthase known to date. [3] Some members of this family have also demonstrated the abili