Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2'-quinazolines.
Novel N-indolylmethyl substituted spiroindoline-3,2'-quinazolines were designed as potential inhibitiors of SIRT1. These compounds were synthesized in good yields by using Pd/C-Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-Y
Pd C-Cu 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione 2-iodoanilides benzene 1,2,3,4-tetrahydroquinazolin N-indolylmethyl substituted spiroindoline-3,2'-quinazolines NH sulfonyl H amino acid Pd C N-indolylmethyl spiroindoline-3,2'-quinazolines SIRT1 Sir 2 mammalian SIRT1 Sir 2 SIRT1