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

doi:10.3390/molecules27092848

Molecules (Apr 2022)

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

DOI: https://doi.org/10.3390/molecules27092848
Journal volume & issue: Vol. 27, no. 9
p. 2848

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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