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

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 IC_50-72h 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.