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 cycloheximide (1, 4-[2(3, 5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl]-2-6-piperidinedione) is able to competitively inhibit hFKBP12 (K-i = 3.4 mu M) and homologous enzymes, a series of derivatives has been synthesized. The effect of the compounds on the activity of hFKBP12 and their cytotoxicity against eukaryotic cell lines (mouse L-929 fibroblasts, K-562 leukemic cells) were determined. As a result, several less toxic or nontoxic cycloheximide derivatives were identified by N-substitution of the glutarimide moiety and exhibit IC50 values in the range of 22.0-4.4 mu M for inhibition of hFKBP12. Among these compounds cycloheximide-N-(ethyl ethanoate) (10, K-i = 4.1 mu M), which exerted FKBP12 inhibition to an extent comparable to that of cycloheximide (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 in a rat sciatic nerve neurotomy model at dosages of 30 mg/kg.