Thioridazine reverts the phenotype in cellular and Drosophila models of amyotrophic lateral sclerosis by enhancing TDP-43 aggregate clearance was written by Cragnaz, Lucia;Spinelli, Greta;De Conti, Laura;Bureau, Emilie A.;Brownlees, Janet;Feiguin, Fabian;Romano, Valentina;Skoko, Natasa;Klima, Raffaella;Kettleborough, Catherine A.;Baralle, Francisco E.;Baralle, Marco. And the article was included in Neurobiology of Disease in 2021.Synthetic Route of C21H27ClN2S2 This article mentions the following:
Brain inclusions mainly composed of misfolded and aggregated TAR DNA binding protein 43 (TDP-43), are characteristic hallmarks of amyotrophic lateral sclerosis (ALS). Irresp. of the role played by the inclusions, their reduction represents an important therapeutic pathway that is worth exploring. Their removal can either lead to the recovery of TDP-43 function by removing the self-templating conformers that sequester the protein in the inclusions, and/or eliminate any potential intrinsic toxicity of the aggregates. The model demonstrated efficient aggregation of endogenous TDP-43, and concomitant loss of its splicing regulation function. We provided a proof-of-principle for its eventual use in high-throughput screening using compounds of the tricyclic family and showed that recovery of TDP-43 function can be achieved by the enhanced removal of TDP-43 aggregates by these compounds We observed that the degradation of the aggregates occurs independent of the autophagy pathway beyond autophagosome-lysosome fusion, but requires a functional proteasome pathway. The in vivo translational effect of the cellular model was tested with two of these compounds in a Drosophila model expressing a construct analogous to the cellular model, where thioridazine significantly improved the locomotive defect. This study also highlights the importance of a two-stage, in vitro and in vivo model system to cross-check the search for small mols. that can clear TDP-43 aggregates in TDP-43 proteinopathies. In the experiment, the researchers used many compounds, for example, Thioridazine hydrochloride (cas: 130-61-0Synthetic Route of C21H27ClN2S2).
Thioridazine hydrochloride (cas: 130-61-0) belongs to piperidine derivatives. Piperidine and its derivatives have become increasingly popular in many synthetic schemes. Piperidine prefers a chair conformation, similar to cyclohexane. Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an axial position, and the other in an equatorial position.Synthetic Route of C21H27ClN2S2
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem