title: Synthesis and cytotoxic evaluation of cycloheximide derivatives as potential inhibitors of FKBP12 with neuroregenerative properties.
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 (K(i) = 3.4 microM) 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 IC(50) values in the range of 22.0-4.4 microM for inhibition of hFKBP12. Among these compounds cycloheximide-N-(ethyl ethanoate) (10, K(i) = 4.1 microM), 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 (IC(50) = 115 microM). 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.
authors.affiliation: Max-Planck Research Unit, Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Christner
authors.forename: R
authors.initials: R
authors.lastname: Wyrwa
authors.forename: S
authors.initials: S
authors.lastname: Marsch
authors.forename: G
authors.initials: G
authors.lastname: Küllertz
authors.forename: R
authors.initials: R
authors.lastname: Thiericke
authors.forename: S
authors.initials: S
authors.lastname: Grabley
authors.forename: D
authors.initials: D
authors.lastname: Schumann
authors.forename: G
authors.initials: G
authors.lastname: Fischer
mesh_terms: D000818:Animals; D003513:Cycloheximide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020104:Immunophilins / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D007700:Kinetics; D051379:Mice; D009416:Nerve Regeneration / Q000187:drug effects*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D003513:Cycloheximide; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins; D019696:Peptidylprolyl Isomerase