Premium
Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin‐dependent protein kinase IV
Author(s) -
Jameel Ehtesham,
Naz Huma,
Khan Parvez,
Tarique Mohd.,
Kumar Jitendra,
Mumtazuddin Syed,
Ahamad Shahzaib,
Islam Asimul,
Ahmad Faizan,
Hoda Nasimul,
Hassan Md. Imtaiyaz
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12898
Subject(s) - pyrimidine , biochemistry , cytotoxicity , calmodulin , kinase , cell culture , chemistry , chemical library , propidium iodide , protein kinase a , docking (animal) , staurosporine , in vitro , biology , enzyme , apoptosis , small molecule , medicine , nursing , programmed cell death , genetics
Calcium/calmodulin‐dependent protein kinase IV ( CAMKIV ) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine‐substituted novel inhibitors of CAMKIV . We successfully synthesized and extensively characterized ( ESI ‐ MS , 1 H NMR , and 13 C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV . Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (Δ G = −11.52 kcal/mol) and binding affinity ( K = 9.2 × 10 10 m −1 ) to the CAMKIV . We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC 50 (39 μ m ) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 μ m on human embryonic kidney cells. To ensure anticancer activity of all these compounds, we further performed propidium iodide assay to evaluate cell viability and DNA content during the cell cycle. We found that compound 1 is again showing a better anticancer activity on both human hepatoma and human embryonic kidney cell lines.