Development of 1-(4-(Substituted)piperazin-1-yl)-2-((2-((4-methoxybenzyl)thio)pyrimidin-4-yl)oxy)ethanones That Target Poly (ADP-Ribose) Polymerase in Human Breast Cancer Cells
Suresha N. Deveshegowda,
Prashant K. Metri,
Rashmi Shivakumar,
Ji-Rui Yang,
Shobith Rangappa,
Ananda Swamynayaka,
Muthu K. Shanmugam,
Omantheswara Nagaraja,
Mahendra Madegowda,
Priya Babu Shubha,
Arunachalam Chinnathambi,
Sulaiman Ali Alharbi,
Vijay Pandey,
Kwang Seok Ahn,
Peter E. Lobie,
Basappa Basappa
Affiliations
Suresha N. Deveshegowda
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Prashant K. Metri
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Rashmi Shivakumar
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Ji-Rui Yang
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
Shobith Rangappa
Adichunchanagiri Institute for Molecular Medicine, BG Nagara, Nagamangala Taluk, Mandya 571448, India
Ananda Swamynayaka
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Muthu K. Shanmugam
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Omantheswara Nagaraja
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Mahendra Madegowda
Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India
Priya Babu Shubha
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Arunachalam Chinnathambi
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
Sulaiman Ali Alharbi
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
Vijay Pandey
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
Kwang Seok Ahn
KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea
Peter E. Lobie
Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
Basappa Basappa
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
A number of uracil amides cleave poly (ADP-ribose) polymerase and therefore novel thiouracil amide compounds were synthesized and screened for the loss of cell viability in a human-estrogen-receptor-positive breast cancer cell line. The synthesized compounds exhibited moderate to significant efficacy against human breast cancer cells, where the compound 5e IC50 value was found to be 18 μM. Thouracil amide compounds 5a and 5e inhibited the catalytical activity of PARP1, enhanced cleavage of PARP1, enhanced phosphorylation of H2AX, and increased CASPASE 3/7 activity. Finally, in silico analysis demonstrated that compound 5e interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology.