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

  • J Med Chem. 2021 Nov 11;64(21):16293-16316. doi: 10.1021/acs.jmedchem.1c01624.
Amit Kumar Jana  1 ,  Jyotsana Singh  2  3 ,  Asha Ganesher  1 ,  Amit Kumar  1 ,  Arpita Banerjee  1 ,  Deepak Kumar  2 ,  Sarvesh Kumar Verma  4 ,  Ashok Kumar Sharma  1 ,  Rabi Sankar Bhatta  4 ,  Rituraj Konwar  2  3 ,  Gautam Panda  1  3
Affiliations
  • 1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, 10 Jankipuram Extension, Sitapur Road, Lucknow, Uttar Pradesh 226031, India.
  • 2. Endocrinology Division, CSIR-Central Drug Research Institute, 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
  • 3. AcSIR-Academy of Scientific & Innovative Research, Ghaziabad 201002, Uttar Pradesh, India.
  • 4. Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, Uttar Pradesh, India.
PMID: 34726897 DOI: 10.1021/acs.jmedchem.1c01624
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.

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