Biological evaluation of a series of thiosemicarbazones targeting the large subunit ribosomal protein eL42 from human 80s ribosomes

Background Thiosemicarbazones are a family known as excellent chelators of enzyme cofactors or molecules with multiple biological activities including anti tumor activity Recent studies by Hountondji rsquo s team has revealed that the large subunit ribosomal protein eL molecular weight of kDa pHi plays a functional role during the elongation step of translation and is over expressed in most cancers ndash Method The method used was the one developed by Hountondji et al which converts the OH functional groups at the positions rsquo and rsquo of adenine sugar of the CCA tRNA into a dialdehyde group by oxidation with NaIO Each aldehyde function can form a Schiff base with the amino group of the side chain of K residue of eL which results in a covalent bond after reduction with NaBH crosslinking Results and discussion The results of different experiments the radioactivity and the Western Blot technique performed in this study show that molecules citral phenylthiosemicarbazone piperitone phenylthiosemicarbazone the benzoin phenylthiosemicarbazone and chlorobenzophenone phenylthiosemicarbazone out of thiosemicarbazones tested showed activity by inhibiting the crosslinking reaction between tRNAox and eL These results suggest that the inhibition produced by thiosemicarbazones consist in masking the amino group of the side chain of Lys located in the catalytic site of protein eL preventing Schiff base formation and the crosslinking reaction These results are in accordance with those of Schneider Poetsch et al who found that certain compounds for example cycloheximide bind to the eL protein through their carbonyl function The weaker effects of benzoin phenylthiosemicarbazone and chlorobenzophenone phenylthiosemicarbazone as compared with citral phenylthiosemicarbazone and piperitone phenylthiosemicarbazone are likely to reflect the inaccessibility of the NH of Lys of eL to the thiocarbonyl groups C S of these thiosemicarbazones because of steric hindrance Finally binding assays on Biacore confirmed interactions between active molecules and the human eL protein Conclusion The inhibitory action of thiosemicarbazones on the interaction between the protein eL and tRNAox prevents formation of a Schiff base between the epsilon amino group of Lys and an aldehyde group of tRNAox The Lys residue of eL which contributes to the catalysis of peptide bond formation that represents the key step in the biosynthesis of proteins is a target of choice for small molecule inhibitors Therefore thiosemicarbazones can be used to reduce the rate of protein synthesis in order to block the hyper proliferation of tumor cells Figure