Design, Synthesis and Evaluation of A/C/D-Ring Analogs of the Fungal Metabolite K-76 as Complement Inhibitors

TEODORO SAUL KAUFMAN; RANJAN P SRIVASTAVA; D SINDELAR, ROBERT; SUSANNE M. SCESNEY; C MARSH, HENRY

JOURNAL OF MEDICINAL CHEMISTRY

AMER CHEMICAL SOC

Lugar: Washington; Año: 1995 vol. 38 p. 1437 - 1445

0022-2623

The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-~,5',5',8a'-tetramethylspiro[ l'(2'H)-naphthalene-2(3~-benzofuranl (la; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt IC (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement,s and IC was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of la,c, the natural product was used as a "topographical model" for the design of partial analogs retaining the desired complement inhibiting potency. Therefore, A/C/D-ring analogs have been synthesized, as shown in Scheme 1 using 3-methoxyphenol(3) and limonene chloride (5) as starting materials, which contain functional groups similar to those found on the natural product. The use of (4R)-(+)a-n d (4S)-(-)-limonene chloride (5a,b, respectively) provided two series of compounds differing in the stereochemistry of the C-4 chiral center (limonene moiety numbering). The in vitro assay results of the inhibition of anaphylatoxin production and classical complement-mediated hemolysis revealed that 7-carboxy-2-(R,S)-methyl-21-'-(methylcyclohexen-(4'R)-yl)-4-methoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-12'--m( ethylcyclohexen-( 4'S)-yl)-4-methoxybenzofuran( 13b) were active in the same range of concentrations as the natural product.