Eur J Med Chem 2021 Apr 3;219:113427. Epub 2021 Apr 3.
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch (UTMB), Galveston, TX, 77555, United States. Electronic address:
To further pursue potent Bax activators with better safety profiles for the treatment of breast cancer, structural optimization was conducted based on lead compound CYD-4-61 through several strategies, including scaffold hopping on the 2-nitro-fluorene ring, replacement of the nitro group with bioisosteres to avoid potential toxicity, and further optimization on the upper pyridine by exploring diverse alkylamine linkers as a tail or replacing the pyridine with bioisosteric heterocycles. F-containing compound 22d (GL0388) exhibited a good balance between the activity and toxicity, displaying submicromolar activities against a variety of cancer cell lines with 5.8-10. Read More