New one-pot synthesis of N-fused isoquinoline derivatives by palladium-catalyzed C–H arylation: potent inhibitors of nucleotide pyrophosphatase-1 and -3

Abstract

Various N-fused isoquinoline derivatives were synthesized using a new one-pot reaction of 1-bromo-2-(2,2-difluorovinyl)benzenes with N-H group containing heterocycles followed by intramolecular palladium-catalyzed C-H arylation. The method described gives convenient access to diverse structures of N-fused polycyclic isoquinolines. Sixteen of the synthesized compounds were screened as potential human nucleotide pyrophosphatase/phosphodiesterase 1 and 3 (h-NPP-1 and h-NPP-3) inhibitors. The most effective h-NPP-1 inhibitor showed an IC value as high as 0.36 ± 0.06 μM, whereas the most potent h-NPP-3 inhibitor posessed an inhibitory value of 0.48 ± 0.01 μM. Kinetic and molecular docking studies of both most effective inhibitors were carried out.

Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors

“…7). 91 However, selectivity data vs. other ecto-nucleotidases have not been provided. The SAR studies showed that two methoxy groups at the 2-and 3-positions of the isoquinoline scaffold are important for the inhibitory activity.…”

Deazapurine Analogues Bearing a 1H‐Pyrazolo[3,4‐b]pyridin‐3(2H)‐one Core: Synthesis and Biological Activity

“…In order to investigate the putative binding mode of the selective inhibitors in the homology models of human TNAP, human IAP, human NPP1 and human NPP3, docking studies were carried out. The crystal structure of any of the proteins was not available at the protein databank, therefore, homology models were prepared by our research group . Since these homology modelled structures do not contain any co‐crystallized ligand in their active sites, the site finder of MOE program was used for selection of binding site before molecular docking studies.…”

“…Cell Transfection and Preparation of Membrane Fractions: The process of cell transfection was carried out initially by transfecting human alkaline phosphatase ( h ‐TNAP & h ‐IAP) expressing plasmids or human nucleotide pyrophosphatase/phosphodiesterase ( h ‐NPP1 & h ‐NPP3), expressing plasmids into the COS‐7 cells, respectively, in 10‐cm plates using Lipofectamine. In the next step, the cells were transferred to Dulbecco's modified Eagle's medium (DMEM) containing 6 µg of plasmid DNA and 24 µL of Lipofectamine reagent.…”

“…Selection of Protein Structure: Ligand‐bound crystallographic structures of h ‐TNAP, h ‐IAP, h ‐NPP1 and h ‐NPP3 are not available in the Protein Data Bank (PDB) so in this study, recently reported homology models from our group were used for docking . The site finder of MOE software was used for selections of binding site before carrying out docking studies, as catalytic zinc ions were important in respect of interactions within the active site .…”

Structural basis for nucleotide recognition by the ectoenzyme CD203c

“…Despite these multiple possible roles, the biochemistry of NPP3 has not been extensively characterized, and the determinants of its substrate specificity are unknown. The 3D structures of all the other mammalian NPPs have been elucidated [11,[22][23][24][25][26][27][28], whereas NPP3 has been the subject of modeling studies to assist isozyme-specific inhibitor design [29][30][31]. Here, we report the crystal structure of human NPP3 as well as its complex with a substrate analog, and explore the dimerization properties of this enzyme.…”