Structure-activity relationship for bromoindole carbaldehydes: Effects on the sea urchin embryo cell cycle

Natural derivatives of indole-3-carbaldehyde were isolated from the tropica l marine ascidian Stomoza murrayi. A series of 13 derivatives, three natura l and 10 synthetic (brominated and N-methylated), were examined for their e ffects on cell division of sea urchin eggs. These derivatives were shown to inhibit the first mitotic cycle in a concentration-dependent manner. By co mparing the IC50 values with the structure of the various molecules, we wer e able to determine that bromination increased the cytotoxicity of the comp ound with a maximum occurring when bromine was added to carbon number 2, wh ile addition of N-methylation was shown to markedly reduce the cytotoxicity of these same compounds brominated at carbon 2 only. Biological activity o f this family of compounds has been characterized, via detailed study of ad dition of the most active derivative, 2,5,6-tribromoindole-3-carbaldehyde, on macromolecule synthesis and cytoskeleton reorganization during the first mitotic cycle of fertilized sea urchin eggs. Fluorescence localization of chromatin and microtubules revealed that 2,5,6-tribromoindole-3-carbaldehyd e allowed pronuclei migration and fusion but prevented the condensation of chromatin, nuclear envelope breakdown, and bipolar mitotic spindle assembly , inducing an arrest of sea urchin embryogenesis at the beginning of mitosi s. It is postulated here that this phenotype is likely to be due to a stron g inhibition of DNA replication and protein synthesis.