CHARACTERIZATION OF NOVEL INDENOINDOLES .1. STRUCTURE-ACTIVITY-RELATIONSHIPS IN DIFFERENT MODEL SYSTEMS OF LIPID-PEROXIDATION

Structure-activity relationships are presented for some representative compounds from a novel series of potent inhibitors of lipid peroxidat ion. The compounds are indenoindole derivatives with oxidation potenti als in organic solvents of between 0.2 and 1.5 V. Two of these compoun ds, b-tetrahydro-9-methoxy-7-methylindeno[2,1-b]indole (H 290/51) with an oxidation potential of 0.32 V and 0-tetrahydro-8-methoxy-6-methyli ndeno[1,2-b]indole (H 290/30) with an oxidation potential of 0.30 V, h ave been tested more extensively and compared with reference compounds in several pharmacological models of lipid peroxidation. The inhibito ry potencies (pIC(50)) of the compounds in respect to Fe/Ascorbate-ind uced production of thiobarbituric acid-reactive substances (TBARS) in a suspension of purified soybean lecithin were calculated These data a re 8.2 for H 290/51; 8.0 for H 290/30; 5.6 for vitamin E; and 6.6 for butylated hydroxytoluene (BHT). In isolated rat renal tissue subjected to hypoxia and reoxygenation, the potency for inhibition of TBARS for mation is 6.9 for H 290/51, 6.9 for H 290/30, and < 5 for vitamin E. I n oxidative modification of low-density lipoproteins (LDL) induced by mouse peritoneal macrophages, the corresponding pIC(50) values for TBA RS inhibition for each compound are: 8.7, 8.3, < 5, and 6.9, respectiv ely. It is concluded that the synthetic indenoindoles are potent antio xidants. The results suggest that indenoindoles such as H 290/51 and H 290/30 could be useful as therapeutic agents in pathophysiological si tuations where lipid peroxidation plays an important role.