Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells
Divakar Vishwanath,
Zhang Xi,
Akshay Ravish,
Arunkumar Mohan,
Shreeja Basappa,
Niranjan Pattehalli Krishnamurthy,
Santosh L. Gaonkar,
Vijay Pandey,
Peter E. Lobie,
Basappa Basappa
Affiliations
Divakar Vishwanath
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India
Zhang Xi
Shenzhen Bay Laboratory, Shenzhen 518055, China
Akshay Ravish
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India
Arunkumar Mohan
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India
Shreeja Basappa
Department of Chemistry, BITS–Pilani Hyderabad Campus, Jawaharnagar 500078, Medchal, Telangana, India
Niranjan Pattehalli Krishnamurthy
NMR Research Centre, Indian Institute of Science, Bangalore 560012, Karnataka, India
Santosh L. Gaonkar
Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
Vijay Pandey
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
Peter E. Lobie
Shenzhen Bay Laboratory, Shenzhen 518055, China
Basappa Basappa
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India
Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC50 value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer.
