Design of Two New Sulfur Derivatives of Perezone: In Silico Study Simulation Targeting PARP-1 and In Vitro Study...

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Poly-ADP-Ribose Polymerase-1 (PARP-1) is overexpressed in various carcinomas, making it a target for cancer therapy.
• Developing effective PARP-1 inhibitors is crucial for advancing cancer treatment strategies.

Purpose of the Study:

• To design and synthesize novel sulfur-containing perezone derivatives as potential PARP-1 inhibitors.
• To evaluate the in vitro inhibitory activity and anticancer potential of synthesized compounds against PARP-1 and cancer cell lines.

Main Methods:

• Synthesis of compounds 8-10 via Michael addition using perezone as a substrate.
• Molecular dynamics (MD) simulations and quantum chemistry studies of natural perezone derivatives.
• Molecular docking studies of eleven sulfur derivatives of perezone.
• In vitro evaluation of PARP-1 inhibitory activity (IC50) and cytotoxicity against MDA-MB-231 and MCF-7 cells.
• Density Functional Theory (DFT) calculations for reactivity property analysis.

Main Results:

• Compounds 8-10 were successfully synthesized.
• Compound 9 exhibited the most potent PARP-1 inhibition with an IC50 of 0.317 µM.
• Compound 9 demonstrated significant inhibitory activity against MDA-MB-231 (145.01 µM) and MCF-7 (83.17 µM) cells.
• DFT calculations indicated that compound 9 possesses optimal properties for binding to PARP-1.

Conclusions:

• The synthesized compound 9 is a promising candidate for PARP-1 inhibition and warrants further investigation for cancer therapy.
• The study highlights the potential of sulfur derivatives of perezone as effective PARP-1 inhibitors.