Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 Breast Cancer Cell Viability

Abstract

Background: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways. Objective: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anti-cancer activities. Methods: Compounds were tested by cell free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer and L929 fibroblast cell lines. Results: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity. Conclusion: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells and further research will enlighten the underlying mechanisms of their effects.

Synthesis and evaluation of 2‐(4‐[4‐acetylpiperazine‐1‐carbonyl] phenyl)‐1H‐benzo[d]imidazole‐4‐carboxamide derivatives as potential PARP‐1 inhibitors and preliminary study on structure‐activity relationship

“…A. Selen Gurkan‐Alp et al synthesized three compounds with (piperazine‐1‐carbonyl)phenyl)‐1H‐benzo[d]imidazole‐4‐carboxamide as the skeleton. But little useful information about structure–activity relationship could be obtained because of the minority amount (Gurkan‐Alp et al, 2020). Herein, 1H‐benzo[d]imidazole‐4‐carboxamide was used as the model skeleton to improve the structure–activity relationships about the substituents in the hydrophobic pocket.…”

Recent progress of research on anti‐tumor agents using benzimidazole as the structure unit

“…When the DNA damage occurred, the PARP, as a molecular receptor for DNA damage, was activated which can recognize and bind to the DNA break site, followed by activating and catalyzing the poly‐ADP ribosylation of the receptor protein to participate in the DNA repair process. PARP inhibitors are cancer therapies that target poly‐ADP ribose polymerase (Elmasry et al, 2019; Gurkan‐Alp et al, 2020).…”

Synthesis, biological evaluation, and molecular modeling studies of new benzoxazole derivatives as PARP-2 inhibitors targeting breast cancer

“…It represented the second most common cause of cancer-related deaths, after liver cancer, with a mortality rate of around 11% 2 . Because breast cancer is a heterogeneous disease showing differentiation in phenotypes and morphological features and leading to various clinical conducts; various options are used for treatment including surgical interventions, radiotherapy, chemotherapy and hormonal therapy 3 , 4 .…”

“…Breast cancer treatment with a group of drugs called Poly (ADP-ribose) polymerase (PARP) inhibitors exhibited promising results; they can be used alone or in combination with other chemotherapeutic agents or radiotherapy 4 . PARP family is a group of proteins involved in many critical cellular processes including DNA single-strand break (SSB) repair and cell death control 5 , 6 .…”