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.

Mechanistic Studies of Semicarbazone Triapine Targeting Human Ribonucleotide Reductase in Vitro and in Mammalian Cells

“…5B). All samples were then incubated for an additional 3 h. This time frame also limits the off-target effects from CHX-induced cytotoxicity (54). Western blot analyses showed that the addition of CHX, as expected, decreased the steadystate level of ␤ 2 by ϳ60% over 3 h (Fig.…”

A Structural Biology Approach Enables the Development of Antimicrobials Targeting Bacterial Immunophilins

“…These represent attempts to influence protein localization, signaling pathways, and protein activation with smaller lead-like molecules dispossessed of the immunosuppressive effects of FK506 and related macrocycles (20)(21)(22)(23). This work describes our initial efforts to design and characterize small lead-like molecules that can influence the virulence of B. pseudomallei through BpML1 inhibition without compromising host immunity.…”

FKBPs in bacterial infections

“…Cycloheximide, a known inhibitor of eukaryotic protein biosynthesis, was identified by screening a compound library containing structurally diverse secondary metabolites for novel FKBP12 inhibitors (Christner et al, 1999). The authors generated derivatives of this new lead structure with an IC 50 of 3.6 µM in order to reduce its cytotoxic properties.…”