Embryonic Responses to Structurally Related Inhibitors

Abstract

ABSTRACT Seventeen of 27 structurally related compounds which could act as purine or pyrimidine antagonists inhibited embryonic development to different degrees. Several benzotriazoles were found to exert similar effects on embryos, the intensity varying with substituents. Older, more differentiated, stages are more susceptible to the benzotriazoles than are early cleavage stages. Exposure to the benzotriazoles at the blastula stage results in hypomorphic cyclopian development without necrosis. There is always a marked delay in the rate of development. Swelling and loss of cells is found, particularly in neurula and tail-bud stages, and usually is followed by death. These findings suggest that the surface coat is interfered with. All active benzothiadiazoles, benzimidazoles, and quinoxalines have the same effect on the embryo; the intensity of the response varying with substitution. Younger, and particularly cleavage, stages are more susceptible, and resistance increases with age of embryo. Exposed blastula stages are frequently arrested as dwarfed tail-buds showing extensive necrosis, particularly of the nervous system. Rarely is there arrest in neurula stages, or if it occurs, these are abortive neurula-exogastrulae with large yolk-plug, no swelling, and larger-sized cells than is normal for this stage. There is always a selective cellular response: early differentiating and very rapidly dividing cells are most sensitive and become necrotic first, while other cells are enlarged and remain arrested. The type of response is determined by the compound, the degree or intensity of response by the substituted groups. It is greatest if only a single nitro group is substituted in the benzothiadiazoles, benzimidazoles, and benzotriazoles, but not in the quinoxalines in which other substitutions seem to have the same degree of effectiveness. On the other hand, some substituents, amino or diphenyl groups for example, decrease the effectiveness of the quinoxalines and benzimidazoles. No direct correspondence between structure and biological function has been discerned.