Design and Activity of Novel Oxadiazole Based Compounds That Target Poly(ADP-ribose) Polymerase

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 3; p. 703
• Main Authors: Vishwanath, Divakar, Girimanchanaika, Swamy S, Dukanya, Dukanya, Rangappa, Shobith, Yang, Ji-Rui, Pandey, Vijay, Lobie, Peter E, Basappa, Basappa
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-01-2022; MDPI
• Subjects: Apoptosis; Apoptosis - drug effects; Breast cancer; Carcinoma; Caspase-3; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Drug Design - methods; Drug development; Drug Screening Assays, Antitumor; Female; human breast cancer; Humans; Kinases; Ligands; Mammary gland; MCF-7 Cells; nicotinamide; oxadiazole; Oxadiazoles; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Phosphorylation; Poly (ADP-Ribose) Polymerase-1 - drug effects; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerases - drug effects; Poly(ADP-ribose) Polymerases - metabolism; Ribose; oxadiazole; poly(ADP-ribose) polymerase; human breast cancer; nicotinamide
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27030703

Novel PARP inhibitors with selective mode-of-action have been approved for clinical use. Herein, oxadiazole based ligands that are predicted to target PARP-1 have been synthesized and screened for the loss of cell viability in mammary carcinoma cells, wherein seven compounds were observed to possess significant IC
values in the range of 1.4 to 25 µM. Furthermore, compound
inhibited the viability of MCF-7 cells with an IC
value of 1.4µM, when compared to Olaparib (IC
= 3.2 µM). Compound
also decreased cell viability in MCF-7 and MDA-MB-231 cells with IC
values of 15.3 and 19.2 µM, respectively. Treatment of MCF-7 cells with compounds
and
produced PARP cleavage, H2AX phosphorylation and CASPASE-3 activation comparable to that observed with Olaparib. Compounds
and
also decreased foci-formation and 3D Matrigel growth of MCF-7 cells equivalent to or greater than that observed with Olaparib. Finally, in silico analysis demonstrated binding of compound
towardsthe catalytic site of PARP-1, indicating that these novel oxadiazoles synthesized herein may serve as exemplars for the development of new therapeutics in cancer.