Synthesis and cytotoxic evaluation of cycloheximide derivatives as potential inhibitors of FKBDP12 with neuroregenerative properties

On the basis of the new finding that the protein synthesis inhibitor cycloh eximide (1, 4-[2(3, 5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl]-2-6-piperid inedione) is able to competitively inhibit hFKBP12 (K-i = 3.4 mu M) and hom ologous enzymes, a series of derivatives has been synthesized. The effect o f the compounds on the activity of hFKBP12 and their cytotoxicity against e ukaryotic cell lines (mouse L-929 fibroblasts, K-562 leukemic cells) were d etermined. As a result, several less toxic or nontoxic cycloheximide deriva tives were identified by N-substitution of the glutarimide moiety and exhib it IC50 values in the range of 22.0-4.4 mu M for inhibition of hFKBP12. Amo ng these compounds cycloheximide-N-(ethyl ethanoate) (10, K-i = 4.1 mu M), which exerted FKBP12 inhibition to an extent comparable to that of cyclohex imide (1), was found to cause an approximately 1000-fold weaker inhibitory effect on eukaryotic protein. synthesis (IC50 = 115 mu M). Cycloheximide-N- (ethyl ethanoate) (10) was able to significantly speed nerve regeneration i n a rat sciatic nerve neurotomy model at dosages of 30 mg/kg.