A comparative study of the effects of certain halogenated benzimidazole ribosides on RNA synthesis, cell proliferation, and interferon production.

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Abstract
5-(or 6-)Bromo-4,5-(or 5,7-)dichloro-1-.beta.-D-ribofuranosylbenzimidazole, 5,6-dibromo-1-.beta.-D-ribofuranosylbenzimidazole and 5,6-dichloro-1-.beta.-D-ribofuranosylbenzimidazole show closely similar structure-activity relationships with respect to inhibition of cellular RNA synthesis, cellular proliferation and influenza virus multiplication, and with respect to enhancement of interferon production. The activities of these compounds are ranked 20:2.5:1. The log dose-response curves constructed for inhibition of FS-4 [human fibroblasts] cell RNA synthesis show similar slopes and a leveling off at 60-70% inhibition of RNA synthesis at the highest concentrations of each compound tested. These 3 derivatives may act through the same mechanism. The concentrations of the benzimidazole ribosides at which the rate of FS-4 proliferation was reduced by 50% are as follows: monobromodichloro: 1.7 .mu.M (0.68 .mu.g/ml); dibromo: 12 .mu.M (4.9 .mu.g/ml); dichloro: 38 .mu.M (12 .mu.g/ml). All compounds reduced the exponential rate of cell proliferation in a dose-dependent manner. The inhibition of cell growth was reversible upon removal of the compounds from the medium. Protocols based on any one of the 3 halobenzimidazole ribosides give interferon yields from poly(I).cntdot.poly(C)-induced FS-4 cells which are comparable to the high yields obtained with the conventional cycloheximide-actinomycin D protocol. The enhancement of interferon yield depends on blocking of the synthesis of RNA which is involved in the shutoff of interferon production.