Synthesis and Cytotoxic Evaluation of Cycloheximide Derivatives as Potential Inhibitors of FKBP12 with Neuroregenerative Properties

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Abstract
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 (Ki = 3.4 μM) 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 μM for inhibition of hFKBP12. Among these compounds cycloheximide-N-(ethyl ethanoate) (10, Ki = 4.1 μM), 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 μM). 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.