Design and Evaluation of NSAID Derivatives as AKR1C3 Inhibitors for Breast Cancer Treatment through Computer-Aided...

Area of Science:

• Oncology
• Medicinal Chemistry
• Biochemistry

Background:

• Breast cancer presents significant global health challenges, including high mortality and treatment resistance.
• Chemotherapy resistance, particularly to anthracyclines like doxorubicin, is a major obstacle in breast cancer treatment.
• The Aldo-keto reductase family 1 member C3 enzyme is implicated in resistance to anthracyclines.

Purpose of the Study:

• To identify novel drug candidates effective against chemotherapy-resistant breast cancer.
• To develop compounds structurally similar to celecoxib with improved efficacy and safety profiles.
• To investigate the potential of compound C-6 as a breast cancer therapeutic.

Main Methods:

• Quantitative structure-activity relationship (QSAR) modeling using artificial neural networks (ANNs) for virtual drug screening.
• Structure-based virtual screening to identify molecules with high enzyme affinity.
• Synthesis and biological evaluation of the lead compound C-6, including cytotoxicity assays on cancer and healthy cell lines.

Main Results:

• Virtual screening identified C-6 with superior enzyme affinity (-11.4 kcal/mol) and a lower half-maximal inhibitory concentration (1.7 µM) compared to celecoxib.
• Compound C-6 was synthesized with an 82% yield.
• C-6 exhibited significant cytotoxic effects on MCF-7 breast cancer cells (62% inhibition) and a less harmful impact on healthy L929 cells compared to doxorubicin and celecoxib.

Conclusions:

• Compound C-6 demonstrates potent anti-cancer activity against breast cancer cells.
• C-6 exhibits a more favorable safety profile than doxorubicin and celecoxib, indicating reduced toxicity to healthy cells.
• C-6 represents a promising novel therapeutic agent for overcoming chemotherapy resistance in breast cancer treatment.