Synthesis of Quinoline Derivatives as Nucleoside Triphosphate Diphosphohydrolases Inhibitors and Development of Ruthenium and Boron Mediated Reaction Methodologies

Abstract

Nucleoside triphosphate diphosphohydrolases (NTPDases) are the extracellular enzymes which catalyze the hydrolysis of extracellular nucleotides. However, over-expression of NTPDases is linked with various pathological diseases such as cancer. Therefore, inhibitors of NTPDases are required to treat the diseases caused by over-expression of these enzymes. In the present research study, a series of quinoline derivatives were synthesized by using molecular iodine as catalyst and their activity as NTPDase inhibitor was analyzed against four isoenzymes of h-NTPDases and ICso were calculated. Among synthesized derivatives many showed promising activities against four isoenzymes of human nucleoside triphosphate diphosphohydrolases. These quinoline derivatives had ICso CuM) values in the range of 0.20-1.75, 0.77-2.20, 0.36-5.50 and 0.90-1.82 for NTPDasel, NTPDase2, NTPDase3 and NTPDase8, respectively. Some derivatives were also selective towards these enzymes. Most active compounds were later analyzed for their mode of inhibition and binding interactions through molecular docking studies. Different transition metals such as Zn, Cu, Ag, Au and Co has been reported to catalyze the enantioselective addition of alkynes to isatin. A new catalyst system based on [Ru(COD)Cl)2]n catalyst with chiral (R)-Hs-BINAP ligand was developed for the synthesis of chiral 3-alkynyl-3-hydroxyindolin-2-ones. Ruthenium acetylides synthesized in situ by C-H activation of terminal alkynes were added across different substituted isatins. The chiral 3-alkynyl-3 hydroxyindolin-2-one derivatives were obtained in good to excellent yields (up to 98%) with high enantioselectivities (up to 92%). Azetidine is a very important four-membered nitrogen based heterocycle. The azetidine moiety is featured in several pharmaceuticals. Besides its immense medicinal importance, synthetic methodologies to synthesize this scaffold are rare. Employing lithiation-borylation methodology, synthesis of azetidine boronic esters was achieved. Ring strain of azabicyclo [1.1.0] butane was exploited for synthesis of this four membered nitrogen heterocycle. Synthesized boronic esters were later transformed into different azetidine based compounds.