Discovery of oxazine-linked pyrimidine as an inhibitor of breast cancer growth and metastasis by abrogating NF-κB activation

  • Front Oncol. 2024 Jul 29:14:1390992. doi: 10.3389/fonc.2024.1390992.
Jie Yuan  1 ,  Bhanuprakash C Narasimhachar  2  3 ,  Akshay Ravish  3 ,  Li Yang  4 ,  Hua Zhang  1 ,  Qun Wang  1 ,  Zhi Li  1 ,  Jun Huang  1 ,  Bei Wang  1 ,  Geng Wang  1 ,  Keshav Kumar Harish  5 ,  Arunachalam Chinnathambi  6 ,  Chandramohan Govindasamy  7 ,  Mahendra Madegowda  5 ,  Basappa Basappa  3
Affiliations
  • 1. Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
  • 2. Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, Karnataka, India.
  • 3. Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, India.
  • 4. Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
  • 5. Department of Studies in Physics, University of Mysore, Mysore, India.
  • 6. Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.
  • 7. Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
PMID: 39135991 DOI: 10.3389/fonc.2024.1390992
Abstract

Introduction: Nuclear factor kappa (NF-κB) plays a key role in Cancer cell proliferation; thus, small molecule inhibitors of NF-κB activity can effectively inhibit breast Cancer (BC) progression. We have previously reported oxazine and piperazine-linked pyrimidines as novel anti-cancer agents that can suppress NF-κB activation in BC cells. Moreover, the TRX-01 compound, an oxazine-linked pyrimidine, inhibited MCF-7 cells at a concentration of 9.17 µM in the Alamar Blue assay.

Methods: This work involved the analysis of frontier molecular orbitals, HOMO-LUMO interactions, and molecular electrostatic potential for the TRX-01 structure. Additionally, the TRX-01 compound was studied for cytotoxicity, and migration as well as invasion assays were performed on BC cells.

Results: Finally, TRX-01 blocked the translocation of NF-κB from the cytoplasm to the nucleus in MCF-7 cells and reduced NF-κB and IκBα levels in a dose-dependent manner. It also suppressed migratory and invasive properties of BC cells.

Conclusion: Overall, the data indicates that TRX-01 can function as a novel blocker of BC growth and metastasis by targeting NF-κB activation.

Keywords
NF-κB activation; TRX-01; breast cancer; cell viability and motility; heterocyclic compounds; molecular orbital analysis; nuclear factor-κB; oxazine linked pyrimidine.
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