Bayan Zoatier
Bayan Zoatier¹, K. Gizem Yildiztekin², M. Abdullah Alagoz³, Ceylan Hepokur⁴, Serdar Burmaoglu⁵, Oztekin Algul¹˒⁶
¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin, Türkiye
² Department of Toxicology, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye ³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Inonu University, Malatya, Türkiye
⁴ Department of Biochemistry, Faculty of Pharmacy, Sivas Cumhuriyet University, Sivas, Türkiye
⁵ Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Türkiye
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, Erzincan, Türkiye
Development of Potent Type V MAPK Inhibitors: Design, Synthesis, and Biological Evaluation of Benzothiazole Derivatives Targeting p38α MAPK in Breast Cancer Cells
Background:
The p38α mitogen-activated protein kinase (p38α MAPK) pathway plays an important role in regulating cellular processes involved in cancer development and progression. Type V MAPK inhibitors represent a promising strategy because they can interact with both the ATP-binding site and an additional allosteric lipid-binding region, potentially improving target selectivity.
Objectives:
This study aimed to design, synthesize, and evaluate benzothiazole derivatives as potential Type V p38α MAPK-targeting compounds with antiproliferative activity against breast cancer cells.
Methods:
A series of 28 benzothiazole derivatives was synthesized and evaluated for antiproliferative activity against estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells, together with normal L929 fibroblast cells, using the MTT assay. The most active compounds were further investigated for their effects on p38α MAPK levels. Molecular docking and 100 ns molecular dynamics simulations were performed to analyze binding interactions and stability within the p38α MAPK binding regions.
Results:
Several benzothiazole derivatives demonstrated promising antiproliferative activity. Compounds 15 and 19 showed the strongest activity against MCF-7 cells, with IC₅₀ values of 8.83 ± 0.43 and 6.19 ± 1.05 μM, respectively. Compound 19 exhibited favorable selectivity indices against MCF-7 (SI = 15.17) and MDA-MB-231 (SI = 8.74) cells. Compounds 19 and 15 showed reduced p38α MAPK levels of 0.112 and 0.155 ng/μg protein, respectively. Molecular docking revealed favorable interactions of these compounds within both ATP-binding and lipid-binding regions of p38α MAPK, while molecular dynamics simulations demonstrated stable protein–ligand interactions throughout the 100 ns simulation period.
Conclusion:
This study identified benzothiazole derivatives as promising p38α MAPK-targeting compounds with antiproliferative activity against breast cancer cells. The integration of biological evaluation and computational analysis supports further optimization of these compounds as potential anticancer lead structures.
Keywords:
Benzothiazole derivatives; p38α MAPK; Antiproliferative activity; Breast cancer; Molecular docking