Design, synthesis, and characterization of α, β‐unsaturated carboxylic acid, and its urea based derivatives that explores novel epigenetic modulators in human non‐small cell lung cancer A549 cell line

Abstract

Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non-histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨ ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

“…It facilitated the expression of procaspase 8, FasL/Fas, and TNF-α to activate the extrinsic pathway and upregulated Bax, downregulated Bcl-2, thereby releasing Cyt-C to activate the intrinsic pathway. 65 In non-small cell lung cancer (NSCLC) cell lines, after pemetrexed treatment, the expression of TNFRSF10B and a vesicular trafficking regulator protein, yip domain family 2 (YIPF2), was increased. YIPF2 facilitated chemotherapeutic drug-mediated apoptosis by promoting TNFRSF10B cell membrane circulation in NSCLC.…”