2. Academic Validation
  3. Discovery of a new hydrazone-oxamide hybrid capable of inducing necroptotic cell death in triple negative breast cancer cells

Discovery of a new hydrazone-oxamide hybrid capable of inducing necroptotic cell death in triple negative breast cancer cells

  • Bioorg Chem. 2025 Apr:157:108267. doi: 10.1016/j.bioorg.2025.108267.
Romina Akhavan 1,  Sanaz Jabari Harsini 2,  Samira Shafiee 3,  Mahya Eftekhari 2,  Raheleh Tahmasvand 4,  Fereshteh Taghipour 4,  Zahra Kooshafar 4,  Hiva Mohammadmirzaeizarandi 1,  Misha Salimi 5,  Ali Almasirad 6,  Mona Salimi 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
  • 3 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 4 Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.
  • 5 Department of Biology, Faculty of Converging Sciences and Technology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. Electronic address: almasirad.a@iaups.ac.ir.
  • 7 Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran. Electronic address: salimimona@pasteur.ac.ir.
PMID: 39986105 DOI: 10.1016/j.bioorg.2025.108267
Abstract

The poor prognosis and inefficiency of the therapeutic agents in treating triple negative breast Cancer (TNBC) have raised significant concerns, driving the quest for designing novel and potent chemotherapeutic compounds. In this regard, inducing programmed cell death (PCD) has emerged as a promising approach for breast Cancer therapy. Accordingly, a series of hybrid molecules comprising hydrazone and oxamide moieties (5a-5q) were designed, synthesized, and assessed for their Anticancer activity against various Cancer cells. Among these synthesized hybrids, compound 5q was selected as the lead compound with remarkable ability to disrupt MDA-MB-231 cell growth, achieving an IC50-72h of 9.79 μM, while exhibiting lower toxicity in normal human cells. The in vitro experiments revealed that this compound triggers neither Apoptosis nor Autophagy in TNBC cells. Furthermore, the in vivo outcomes corroborated the in vitro results, showing a significant delay in tumor growth at a dose of 1 mg/kg/day following three weeks of treatment in the 4T1 mouse model of TNBC. The findings of this study suggested that compound 5q acts through Necroptosis by overexpression of P-RIPK3 and phosphorylation of its downstream effector, MLKL. Compound 5q holds promise as a potential candidate for the development of anti-TNBC drugs.

Keywords

Apoptosis; Autophagy; Breast cancer; Cytotoxicity; Molecular hybridization; Necroptosis.

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