Teratological studies in the thalidomide field

Thalidomide-type teratogenicity: structure–activity relationships for congeners

“…Table 2 summarises the findings for the teratogenicity testing of various hydrolysis products of thalidomide (compounds 13-22). 33,42,43 It has been pointed out previously that thalidomide is unstable at pH values above 6-7 and rapidly undergoes spontaneous hydrolysis in vivo to some 12 hydrolysis products. 44,45 There is also some evidence that besides spontaneous hydrolysis there may be additional enzyme-assisted hydrolysis at the amide bonds.…”

“…Thalidomide analogue EM255 [12] 3-(1-Oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2-one Rabbit 37 Table 5 shows 16 compounds (compounds 33-48) in which the phthalimide ring has been left intact with structural modification or replacement of the glutarimido ring. 34,43,47,[50][51][52] All compounds were inactive as teratogens in the pregnant rabbit and two of these chemicals are used as pesticides (compounds 36, 37). The negative findings for N-hydroxythalidomide (com- α-Aminoglutarimide [19] 3-Aminopiperidine-2,6-dione Rabbit 33,42 L-Glutamine [20] ( 2 S)-2,5-Diamino-5-oxopentanoic acid Rabbit 33,42 DL-Glutamine [21] 2,5-Diamino-5-oxopentanoic acid Rabbit 33,42 Phthalic acid [22] Benzene-1,2-dicarboxylic acid Rabbit 33,42 Toxicology Research Review pound 43) and N-methoxythalidomide (compound 44) were a little surprising considering they possess only minor additions to the glutarimido ring, but these observations might be explained if they were to undergo a rapid conjugation with glucuronic acid, the latter after demethylation.…”