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

Abstract

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 IC50 values in the range of 1.4 to 25 µM. Furthermore, compound 5u, inhibited the viability of MCF-7 cells with an IC50 value of 1.4µM, when compared to Olaparib (IC50 = 3.2 µM). Compound 5s also decreased cell viability in MCF-7 and MDA-MB-231 cells with IC50 values of 15.3 and 19.2 µM, respectively. Treatment of MCF-7 cells with compounds 5u and 5s produced PARP cleavage, H2AX phosphorylation and CASPASE-3 activation comparable to that observed with Olaparib. Compounds 5u and 5s 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 5s 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.

The anti‐breast cancer therapeutic potential of 1,2,3‐triazole‐containing hybrids

“…[ 78 ] The phenyl ring on the pyrimidine moiety was not essential for the activity, and hybrid 51 (IC 50 : 5.85 µM, MTT assay) showed promising antiproliferative activity against MCF‐7 breast cancer cells. [ 79 ] In addition, these hybrids could target the histone deacetylases in MCF‐7 breast cancer cells.…”

Electrochemical Synthesis of Versatile Pyrimidine and Oxadiazoles Tethered Triazoles as Inhibitors of VEGFR-2 in Human Breast Cancer Cells

“…Upon cyclizing with CS 2 in ethanolic KOH, 4-methoxyphenyl acetic acid-hydrazide (18) yields oxadiazole-thiol (19), which on propargylation in refluxing acetone in presence of K 2 CO 3 yields (20), which is used to synthesize oxadiazole-triazoles 21(a-f) (Scheme 3).…”

“…Heterocycles have been widely studied and integrated into medicinal chemistry due to their diverse biological activities, including targeting specific cellular pathways, DNA binding, alkylation, and apoptosis induction [4,5]. Presently, extensive research is focusing on various natural and synthetic heterocyclic compounds, such as pyrimidines [6][7][8], coumarins [9,10], pyrazoles [11][12][13], triazoles [14][15][16], oxadiazoles [17][18][19], and piperazines [20,21], among others, which have displayed promising biological properties.…”

Background-Quenched Aggregation-Induced Emission through Electrostatic Interactions for the Detection of Poly(ADP-ribose) Polymerase-1 Activity

“…As the leading PARylation enzyme, poly(ADP-ribose) polymerase-1 (PARP1) is involved in many cellular processes, such as DNA repair, transcriptional regulation and signal transduction [ 1 , 2 ]. The activity of PARP1 is closely related to tumorigenesis and malignant progression and its inhibitors have a wide spectrum of applications in diagnostics and therapeutics [ 3 ]. It has been documented that PARP1 can be regarded as a potential biomarker and therapeutic target for ischemic diseases, cardiac hypertrophy, diabetes, inflammation or neuronal death and some cancers (e.g., ovarian, breast and oral) [ 4 , 5 ].…”