Structure-activity relationship for bromoindole carbaldehydes: effects on the sea urchin embryo cell cycle.
Natural derivatives of indole-3-carbaldehyde were isolated from the tropical marine ascidian Stomoza murravi. A series of 13 derivatives, three natural and 10 synthetic (brominated and N-methylated), were examined for their effects on cell division of sea urchin eggs. These derivatives were shown to inhibit the first mitotic cycle in a concentration-dependent manner. By comparing the IC50 values with the structure of the various molecules, we were able to determine that bromination increased the cytotoxicity of the compound with a maximum occurring when bromine was added to carbon number 2, while addition of N-methylation was shown to markedly reduce the cytotoxicity of these same compounds brominated at carbon 2 only. Biological activity of this family of compounds has been characterized, via detailed study of addition 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-carbaldehyde 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 mitosis. It is postulated here that this phenotype is likely to be due to a strong inhibition of DNA replication and protein synthesis.
Moubax
I
I
Centre de Phytopharmacie, CNRS URA 461, Université de Perpignan, France.
Bontemps-Subielos
N
N
Banaigs
B
B
Combaut
G
G
Huitorel
P
P
Girard
J P
JP
Pesando
D
D
D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D017605:Bromine Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D008297:Male; D010063:Ovum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors; D012617:Sea Urchins / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D013329:Structure-Activity Relationship
D000447:Aldehydes; D017605:Bromine Compounds; D007211:Indoles; D011506:Proteins; D004247:DNA