Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.
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,1H NMR, and13C 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 (ΔG = -11.52 kcal/mol) and binding affinity (K = 9.2 × 1010m-1) to the CAMKIV. We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC50(39 μm) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 μm 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.
Department of Chemistry, B.R. Ambedkar Bihar University, Muzaffarpur, Bihar, India.
Ehtesham
E
Jameel
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Huma
H
Naz
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Parvez
P
Khan
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
Mohd
M
Tarique
Department of Chemistry, Jamia Millia Islamia, New Delhi, India.
Jitendra
J
Kumar
Department of Chemistry, B.R. Ambedkar Bihar University, Muzaffarpur, Bihar, India.
Syed
S
Mumtazuddin
Department of Biotechnology, College of Engineering and Technology, IFTM, Moradabad, India.
Shahzaib
S
Ahamad
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Asimul
A
Islam
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Faizan
F
Ahmad
Department of Chemistry, Jamia Millia Islamia, New Delhi, India.
Nasimul
N
Hoda
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
Md Imtaiyaz
MI
Hassan
D001665:Binding Sites; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013050:Spectrometry, Fluorescence
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4
anticancer activity; calcium/calmodulin-dependent protein kinase IV; drug design and discovery; high-affinity ligands; molecular docking