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

Abstract

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.

A Synthetic Overview of Benzoxazines and Benzoxazepines as Anticancer Agents

“…The desired benzoxazine core 93 was furnished from free amine‐containing bromo derivative by the participation of crucial copper‐catalyzed intramolecular N ‐aryl amination (Figure 15). [39] …”

“…In 2021, our group designed and synthesized tyrosine derived benzoxazine derivatives as an anti‐breast cancer agent. Structure‐activity activity relationship studies, 103 which regressed tumor growth at concentrations of 5 mg/Kg and 20 mg/Kg better than tamoxifen without any mortality in rat syngeneic mammary tumor model, selected as potent compound with IC 50 value 0.20–0.65 μM, that induces apoptosis, cell cycle arrest, loss of mitochondrial membrane potential in breast cancer cells [39] …”

“…[38] In continuing efforts to improve anti-breast cancer agents such as benzoxazepine derivatives, we have recently reported novel tyrosine-derived benzoxazine active in a rat syngenic mammary breast cancer tumour model. [39] The detailed description, as well…”

“…Our group reported amino acids derived benzoxazepines towards accessing nonsteroidal architectures as antitumor agents [38] . In continuing efforts to improve anti‐breast cancer agents such as benzoxazepine derivatives, we have recently reported novel tyrosine‐derived benzoxazine active in a rat syngenic mammary breast cancer tumour model [39] . The detailed description, as well as structural modification, that affect their anticancer activity, are revealed in the main text of this review article.…”

Synthesis of amino acid derived 2-methylene morpholines and 3,4-dihydro-2H-1,4-oxazines via ag (I) promoted intra-molecular cyclization of alkynols

“…Our group is relentlessly working in the area of synthesis and biology of amino acid-derived chiral heterocycles and natural-product-like molecules. [23][24][25][26] In this connection, novel methodologies for the synthesis of substituted piperazine 27 by regioselective ring-opening of amino acid-derived chiral aziridines and diastereoselective synthesis of amino acid derived trans-2,5-disubstituted morpholines, piperazines, and thiomorpholines via I2-Mediated cyclization 28 have been reported. Inspired by these well-developed strategies towards the exploration of natural amino acids, we sought to investigate the reactivity of silver salt on amino acid derived alkynols in order to synthesize diverse oxazines like morpholines via intramolecular cyclization.…”