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

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

Molecules. 2022 Apr 29;27(9):2848. doi: 10.3390/molecules27092848.

Authors

Suresha N Deveshegowda¹, Prashant K Metri¹, Rashmi Shivakumar¹, Ji-Rui Yang², Shobith Rangappa³, Ananda Swamynayaka⁴, Muthu K Shanmugam⁵, Omantheswara Nagaraja⁴, Mahendra Madegowda⁴, Priya Babu Shubha⁶, Arunachalam Chinnathambi⁷, Sulaiman Ali Alharbi⁷, Vijay Pandey², Kwang Seok Ahn^{8

9}, Peter E Lobie^{2

10

11}, Basappa Basappa¹

Affiliations

¹ Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
² Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
³ Adichunchanagiri Institute for Molecular Medicine, BG Nagara, Nagamangala Taluk, Mandya 571448, India.
⁴ Department of Studies in Physics, University of Mysore, Manasagangotri, Mysore 570006, India.
⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
⁶ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
⁷ Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
⁸ KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea.
⁹ Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.
¹⁰ Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
¹¹ Shenzhen Bay Laboratory, Shenzhen 518055, China.

Abstract

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.

Keywords: PARPi; apoptosis; breast cancer; thiouracil amides.

MeSH terms

Adenosine Diphosphate
Amides
Breast Neoplasms* / drug therapy
Cell Line, Tumor
Female
Humans
Piperazine
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases* / metabolism
Ribose
Thiouracil

Substances

Amides
Piperazine
Thiouracil
Adenosine Diphosphate
Ribose
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases

Grants and funding

This work was supported by DBT-NER, and Vision Group on Science and Technology (CESEM), Government of Karnataka. This work was also supported by the Shenzhen Key Laboratory of Innovative Oncotherapeutics (ZDSYS20200820165400003) (Shenzhen Science and Technology Innovation Commission), China; Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434), China; Overseas Research Cooperation Project (HW2020008) (Tsinghua Shenzhen International Graduate School), China; Tsinghua University Stable Funding Key Project (WDZC20200821150704001); the Shenzhen Bay Laboratory (21310031), China and TBSI Faculty Start-up Funds, China. This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2021R1I1A2060024). This project was supported by Researchers Supporting Project number (RSP-2022/5) King Saud University, Riyadh, Saudi Arabia.