Tyrosine-Derived Novel Benzoxazine Active in a Rat Syngenic Mammary Tumor Model of Breast Cancer

In continuing efforts of improving benzoxazepine derivatives as an anti-breast Cancer agent, a new chemical entity, benzoxazine, was designed from scaffold morphing. Structure-activity relationship studies revealed that H, -OMe, -CF₃, and -F were well tolerated on R₁ and R₂ positions of ring A, and R² as -CH₂CH₂N(CH₂)₄ (N-ethyl pyrrolidine) and -CH₂CH₂N(CH₂)₅ (N-ethyl piperidine) chains on ring D increased activities (Series B, Figure 3). 13d selected as a lead compound (IC₅₀: 0.20 to 0.65 μM) induces Apoptosis, cell cycle arrest, and loss of mitochondrial membrane potential in breast Cancer cells. Compound 13d was formulated into 13d-f using cyclodextrin to improve its solubility for a pharmacokinetic, in vivo efficacy study. Both 13d and 13d-f regressed tumor growth at concentrations of 5 and 20 mg/kg better than tamoxifen without any mortality in a rat syngenic mammary tumor model. Collectively, our data suggest that tyrosine-derived novel benzoxazine 13d could be a potential lead for the treatment of breast Cancer and hence deserve further in-depth studies.