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. 2022 Apr 29;27(9):2848.
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

Suresha N Deveshegowda  1 , Prashant K Metri  1 , Rashmi Shivakumar  1 , Ji-Rui Yang  2 , Shobith Rangappa  3 , Ananda Swamynayaka  4 , Muthu K Shanmugam  5 , Omantheswara Nagaraja  4 , Mahendra Madegowda  4 , Priya Babu Shubha  6 , Arunachalam Chinnathambi  7 , Sulaiman Ali Alharbi  7 , Vijay Pandey  2 , Kwang Seok Ahn  8   9 , Peter E Lobie  2   10   11 , Basappa Basappa  1
Affiliations

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 et al. Molecules. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthesis of thiouracil containing amide derivatives.
Figure 1
Figure 1
Loss of MCF-7 cell viability produced by compounds 5a, 5b, 5e, and 5f. MCF-7 were exposed to 5a (A), 5b (B), 5e (C), and 5f (D) for 72 h and the viability of cells was analyzed by Alamar Blue assays. The results are presented as mean ± S.E.M. of triplicate determinations.
Figure 2
Figure 2
Compounds 5a, 5e, and 3-aminobenzamide inhibited the PARP1 catalytic activity. Graphical representation of the inhibition of the catalytic activity of PARP1 by indicated compounds (n = 3). Data are expressed as mean ± SEM.
Figure 3
Figure 3
Compounds 5a, 5e, and Olaparib cleave PARP1 (A) and increase phosphorylation of H2A-X (B) and CASPASE-3/7 activity (C) in MCF-7 cells. MCF-7 cells were treated with or without compounds 5a, 5e, or Olaparib at the indicated concentrations. The respective protein bands were detected by Western blot analysis. GAPDH or β-ACTIN were used as input controls. Data are expressed as mean ± SEM. ** p ≤ 0.01; *** p ≤ 0.001.
Figure 4
Figure 4
The HOMO and LOMO of molecule 5e obtained by the DFT/B3LYP/6-31+G (d,p) method.
Figure 5
Figure 5
Molecular electrostatic potential surfaces of compound 5e.
Figure 6
Figure 6
Cartoon representation of PARP1 with compound 5e (A) and its 2D interactions (4HHY) (B).
Figure 7
Figure 7
3D surface view of PARP1 and compound 5e and a zoomed view of the compound 5e in the active site cavity.
Figure 8
Figure 8
RMSD plot of ligand 5e and PARP1.
Figure 9
Figure 9
RMSF plot of protein molecule (4HHY) PARP1.
Figure 10
Figure 10
(a) Compound 5e-PARP1 interaction and (b) histogram charts of the interaction percentages of the MD simulation for the complex.
Figure 10
Figure 10
(a) Compound 5e-PARP1 interaction and (b) histogram charts of the interaction percentages of the MD simulation for the complex.
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