RESUMO
A DABCO catalyzed aza-Michael addition of thiazolidine-2,4-dione to a variety of electron deficient alkenes has been developed. Additionally, a DABCO/succinic acid salt system has been designed that allows for the one pot tandem aza-Michael/Knoevenagel reaction of thiazolidine-2,4-dione to give difunctionalized thiazolidine-2,4-dione products. To the best of our knowledge, this is the first example of a one-pot tandem aza-Michael/Knoevenagel reaction involving thiazolidine-2,4-dione.
Assuntos
Alcenos , Ácido Succínico , Catálise , Elétrons , Estrutura Molecular , Piperazinas , Tiazolidinedionas , TiazolidinasRESUMO
The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.