Design, synthesis, and preliminary anticancer evaluation of diphenylpropan-1-one derivatives: in vitro, in vivo and in silico studies

Abstract

Breast cancer is a leading cause of cancer-associated mortality and morbidity worldwide, and there is a continued need for structurally diverse anticancer agents with improved properties. The present study reports a series of diphenylpropan-1-one (DPP) derivatives (4a–4i), rationally designed around a chalcone framework and synthesized via a three-step reaction sequence. The physicochemical and spectral characterization of the synthesized derivatives was performed using spectral techniques. Their anticancer potential was evaluated through a preliminary in vitro cytotoxicity screening against the MCF-7 mammary cancer cell line, followed by an in vivo efficacy assessment using a DMBA-induced mammary cancer animal model. To explore a possible molecular target, in silico molecular docking was performed against the epidermal growth factor receptor (EGFR) tyrosine kinase domain as an exploratory computational analysis. Amongst the synthesized derivatives, compound 4h demonstrated the most potent cytotoxic effects (IC50 = 1.7 µg mL−1), comparable to the standard drug gefitinib (IC50 = 1.8 µg mL−1). The in vivo studies revealed a significant and dose-dependent decline in cellular proliferation and mammary gland tumor progression, along with histopathological abnormalities upon treatment with compound 4h. Interestingly, the quantitative gene expression analysis demonstrated a significant reduction in the DMBA-induced overexpression of BRCA1, BRCA2, and TP53 in the 4h-treated groups in a dose-dependent manner. Molecular docking studies showed favorable binding of the DPP derivatives within the EGFR active site, with compound 4h exhibiting strong affinity (binding energy = −9.2 kcal mol−1) and favorable predicted interactions in the ATP-binding region of EGFR. Computational ADMET profiling provided additional preliminary predictions of the pharmacokinetic and toxicity properties of compound 4h. The identified DPP derivatives demonstrated encouraging preliminary anticancer potential and may serve as promising lead molecules for future investigations.