Inhibition of complement by a series of substituted 2-aryl-1,3-indandiones: interaction with the fifth component of complement.
A series of substituted 2-aryl-1,3-indandiones were investigated for their ability to inhibit the complement system. Some of them were found to be considerably strong inhibitors. The inhibitory activity was mainly dependent on substitutions at positions 3 and 5 of the phenyl ring. 3,5-dichloro-(8), 3,5-bis(trifluoromethyl)- (7), 3,5-diisopropyl- (3) and 3,5-di-t-butyl- (5) phenylindandiones were the strongest inhibitors of the series. The generation of EAC1-5 cells from EAC1-3 cells and C5 was most strongly inhibited by these compounds although some inhibition of the interaction of EAC1-5 with C6-C9 and EAC1-6 with C7-C9 was also observed. Slight inhibition at other steps of complement activation was also seen but this was not considered to be appreciable. Dialysis of normal serum or purified C5 pre-incubated with compounds 3, 5, 7 and 8 did not cause recovery of the hemolytic activity of normal serum or purified C5. Thus, the main site of inhibition in the complement cascade appeared to be at C5. The total alternative pathway was also inhibited to some extent by these compounds, probably due to their interaction with C5.
D000818:Animals; D003167:Complement Activation / Q000187:drug effects*; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D011817:Rabbits
D003182:Complement C5; D003169:Complement Inactivator Proteins; D007189:Indans; D007192:Indenes