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Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436,
A Selen Gurkan-Alp1, Mehmet Alp1, Arzu Z Karabay2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06560 Tandogan, Ankara, Turkey.
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)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer 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.
Insights
New Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors show promise for breast cancer treatment. Compounds 6a, 6b, and 8a effectively inhibited cancer cell viability and PARP-1 activity, with 6a and 8a demonstrating low toxicity.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are crucial in treating cancers with DNA repair defects.
- These inhibitors target DNA Damage-Response (DDR) pathways, offering a targeted therapeutic approach.
Purpose of the Study:
- To synthesize and evaluate novel substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[d]imidazole-4-carboxamide compounds as potential PARP-1 inhibitors.
- To assess the anticancer activities and PARP-1 inhibitory potential of these synthesized compounds.
Main Methods:
- Compounds were synthesized and tested for PARP-1 inhibitory activity using a cell-free colorimetric assay.
- Anticancer effects were evaluated using the MTT assay on breast cancer cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468) and a fibroblast cell line (L929).
Main Results:
- Compounds 6a, 6b, and 8a demonstrated significant inhibition of PARP-1 activity.
- Compound 6b effectively inhibited viability in tested breast cancer cells, while 6a and 8a showed specific efficacy against certain cell lines.
- Compounds 6a and 8a exhibited non-toxicity in L929 fibroblast cells, indicating a favorable safety profile.
Conclusions:
- The synthesized compounds 6a, 6b, and 8a possess significant PARP-1 inhibitory activities and anticancer effects against breast cancer cells.
- These compounds represent promising candidates for further investigation into their therapeutic potential and underlying mechanisms in cancer treatment.
