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Ad-3 mutants induced by hycanthone, lucanthone and their indazole analogs, IA-3, IA-4 and IA-5 were studied to characterize the genetic alterations produced by these agents in Neurospora crassa. The results of genetic analysis indicate that, in marked contrast to past experiments with chemical mutagens on heterokaryon 12, all of these antischistosomal agents induce a very high frequency of multilocus deletions.

A sublethal dose of 100 mg lucanthone hydrochioride/kg (Miracil D, Nilodin; NSC-14574) administered ip into Chinese hamsters [median lethal dose for 30-day survival (LD50/30) of 315 mg/kg] reduced the radiation tolerance of the small intestine and had little or no effect on the radiation tolerance of the bone marrow. Lucanthone hydrochloride was administered at various times before and after whole-body 60Co gamma-irradiation. The median lethal dose for 7-day survival (LD50/7), indicative of death from gastrointestinal epithelial denudation, was reduced from 1,235 rads to minimum values of 995 rads or 985 rads by lucanthone hydrochloride inoculation 10 hours before irradiation or 7.5 hours post irradiation, respectively. The LD50/30, indicative of death from bone marrow stem cell depletion, remained unaltered at approximately 990 rads over the entire treatment scheme, which indicated that the radioresponsiveness of bone marrow stem cells was unaffected by lucanthone hydrochloride. The lucanthone hydrochloride effect was reversible in that control values of LD50/7 were attained by 40 hours post inoculation. Serum concentration of lucanthone hydrochloride in the Chinese hamster, determined spectrophotometrically, reached a peak of 8 microgram/ml by 1.5 hours post inoculation and then decreased exponentially with a half-life of approximately 6 hours, so that by 30 hours post inoculation it was unmeasurable.

N-Oxidation at the diethylamino group of hycanthone, of lucanthone, and of two chlorobenzothiopyranoindazoles resulted in a marked reduction in mutagenic activity, while antischistosomal activity was retained or even enhanced. Introduction of chlorine into the 8-position of benzothiopyranoindazoles reduced acute toxicity but had no effect on chemnotherapeutic potency. These dissociations of biological activities indicate that safer antischistosomal compounds of this class can be developed.