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

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 9; p. 2848
• Main Authors: Deveshegowda, Suresha N, Metri, Prashant K, Shivakumar, Rashmi, Yang, Ji-Rui, Rangappa, Shobith, Swamynayaka, Ananda, Shanmugam, Muthu K, Nagaraja, Omantheswara, Madegowda, Mahendra, Babu Shubha, Priya, Chinnathambi, Arunachalam, Alharbi, Sulaiman Ali, Pandey, Vijay, Ahn, Kwang Seok, Lobie, Peter E, Basappa, Basappa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29-04-2022; MDPI
• Subjects: Adenosine Diphosphate; Amides; Apoptosis; Binding sites; Breast cancer; Breast Neoplasms - drug therapy; Caspase-3; Cell Line, Tumor; Cell viability; Enzymes; Estrogens; Female; Humans; PARPi; Phosphorylation; Piperazine; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Ribose; Seeds; Thiouracil; thiouracil amides; Uracil; apoptosis; breast cancer; PARPi; thiouracil amides
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27092848

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
IC
value was found to be 18 μM. Thouracil amide compounds
and
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
interacted with PARP1. Hence, specific thiouracil amides may serve as new drug-seeds for the development of PARP inhibitors for use in oncology.