Teratogenicity, thalidomide

Parman T, Wiley JM, Wells PG (1999) Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5 582-585... 

Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327 1345-1349... 

Arlen RR and Wells PG (1996) Inhibition of thalidomide teratogenicity by acetylsalicylic acid Evidence for prostaglandin H synthase-catalyzed bioactivation of thalidomide to a teratogenic reactive intermediate. Journal of Pharmacology and Experimental Therapeutics 277 1649-1658. 

The glutarimide best known to the lay public, thalidomide (40), owes its reputation not to efficacy, but to the wholly unanticipated and tragic teratogenic effects elicited by this compound. It might be noted that the very efficacy and lack of the usual barbiturate side effects shown by this drug led to its prescription as a hypnotic for expectant mothers. Condensation of the phthalimide of glutamic acid (39) with ammonia at elevated... 

One enantiomer of penicillamine (D-) exhibits antiarthritic properties but foe other is highly toxic (Figure 8.3). The teratogenic effects of thalidomide were induced by one enantiomer, foe other exhibited foe beneficial effects against morning sickness. 

Thalidomide Polycyclic teratogen, antiangiogenic mechanism unknown... 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

Metabolites 4.203 and 4.205 were minor. Metabolite 4.204 was the main product in rats and dogs. Toxicological investigations revealed that, of the twelve hydrolysis products of thalidomide, only the three containing the intact phthalimido moiety show teratogenic activity, namely metabolites 4.202, 4.203, and 4.205) [132] [133],... 

H. J. Schmahl, W. Heger, H. Nau, The Enantiomers of the Teratogenic Thalidomide Analogue EM 12. 2. Chemical Stability, Stereoselectivity of Metabolism and Renal Excretion in the Marmoset Monkey , Toxicol. Lett. 1989, 45, 23-33. 

Thalidomide The (i )-enantiomer is a sedative and the (5)-enantiomer is teratogenic (i.e., causes fetal deformity). 

A well known example of tragic consequences is provided by "Thalidomide" (or "Contergan") which was commercialised in the 60 s whereas the (/ )-enantiomer shows a weak sedative activity, the enantiomer of (5)-configuration, administered together in the racemate, caused in the expectant mothers a teratogenic effect (malformations) on the foetus. 

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