Metalloporphyrins inhibit beta-hematin (hemozoin) formation

Metal-substituted protoporphyrin IXs (Cr(III)PPIX (1), Co(III)PPIX (2), Mn( III)PPIX (3), Cu(II)PPIX (4), Mg(II)PPIX (5), Zn(II)PPIX (6), and Sn(IV)PPI X (7)) act as inhibitors to beta-hematin (hemozoin) formation, a critical d etoxification biopolymer of malarial parasites. The central metal ion plays a significant role in the efficacy of the metalloprotoporphyrins to inhibi t beta-hematin formation. The efficacy of these compounds correlates well w ith the water exchange rate for the octahedral aqua complexes of the porphy rin's central metal ion. Under these in vitro reaction conditions, metallop orphyrins 5, 6 and 7 are as much as six times more efficacious than the fre e ligand protoporphyrin IX in preventing beta-hematin formation and four ti mes as efficacious as chloroquine, while metalloporphyrins 3 and 4 are thre e to four times more effective at preventing beta-hematin formation than th e free protoporphyrin M base. In contrast, the relatively exchange inert me talloporphyrins 1 and 2 are only as efficacious as the free ligand and only two-thirds as effective as chloroquine. Aggregation studies of the heme:MP PIX using UV-Vis and fluorescence spectroscopies are indicative of the form ation of pi-pi hetero-metaloporphyrin assemblies. Thus, hemozoin inhibition is likely prevented by the formation of heme:MPPIX complexes through pi-st acking interactions. The ramifications of such hetero-metalloporphyrin asse mblies, in the context of the emerging structural picture of hemozoin, are discussed. (C) 2000 Elsevier Science Inc. All rights reserved.