Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors.
The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydrox y-2',5',5', 8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt 1c (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement, and 1c was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of 1a,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)-(+)- and (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-2-(1'-methylcyclohexen-(4'R)-yl)-4-met hoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'S)-yl)-4-met hoxybenzofuran (13b) were active in the same range of concentrations as the natural product.
Kaufman
T S
TS
School of Pharmacy, University of Mississippi, University 38677, USA.
Srivastava
R P
RP
Sindelar
R D
RD
Scesney
S M
SM
Marsh
H C
HC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015926:Complement C3a / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003169:Complement Inactivator Proteins / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013191:Stachybotrys / Q000737:chemistry*
D003169:Complement Inactivator Proteins; C093435:K 76 terpene; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D015926:Complement C3a; D015936:Complement C5a