Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR‐γ Partial Agonists by Modulating Epithelial–Mesenchymal Transition in Lung Cancer Metastasis

Abstract

Epithelial‐to‐mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator‐activated receptor (PPAR)‐γ, a ligand‐activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR‐γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR‐γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR‐γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2‐furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR‐γ partial activation. QDs‐treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI‐H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E‐box binding homeobox 1) and concomitant upregulation of epithelial marker (E‐cadherin).

Partial Activation of PPAR‐γ by Synthesized Quercetin Derivatives Modulates TGF‐β1‐Induced EMT in Lung Cancer Cells

“…Recently, our group synthesized a series of Schiff base derivatives of quercetin (Table 1 and Figure 1) and ascertained their effectiveness on EMT markers of A549 cell line. [20] Our study evidenced that EMT process was counteracted via activation of PPAR-𝛾 through the quercetin derivatives (QDs). There are several studies that address the efficiency of PPAR-𝛾 in modulating EMT immune response.…”

“…[5] In the present study, we have strategized to modulate EMT pathway induced by TGF-𝛽1 by the means of partial activation of PPAR-𝛾 with our novel derivatives of quercetin. [20] To the best of our knowledge, this is the first time to show inhibition of TGF-𝛽1-induced EMT in lung cancer cells via PPAR-𝛾 partial activation by chemically synthesized small molecules. The compounds that stimulate PPAR-𝛾 in desired manner, i.e., lesser effect than synthetic agonists and greater effect than weak agonists are referred to as partial agonist.…”

“…We recently demonstrated that all the five newly synthesized QDs functioned as PPAR-𝛾 activators which in turn caused changes in EMT markers in A549 cells. [20] Having verified with PPAR-𝛾 activation by QDs, we next tend to investigate the interplay between PPAR-𝛾, TGF-𝛽1, and synthesized QDs. We evaluated whether the activation of PPAR-𝛾 is affected by QDs on incorporation of TGF-𝛽1 in the cells.…”

“…[15][16][17] On the other hand, synthetic ligands appear to be a promising modality for PPAR-𝛾, namely, thiazolidinediones (TZDs) and nonsteroidal anti-inflammatory drugs (NSAIDs); which act as full agonists leading to an over-activation process [18] causing deteriorating adverse effects like higher risk of the cardiovascular system, [19] edema, water retention, and osteoporosis. [20] Hence, the application has been restricted due to their toxicity profile.…”

“…[16,21] Our previous study successfully reported three partial agonists namely, quercetin thiosemicarbazone (QUETSC), quercetin 2-furoic hydrazone (QUE2FH) and quercetin falicyl hydrazone (QUESH) that activated PPAR-𝛾 in balanced manner, i.e., lower than RSG (full agonist) and higher than quercetin (weak agonist). [20] These Schiff base compounds comprise various biological significance, increased synthetic flexibility, and provide great resemblance for natural molecules. A study conducted by Naidu and Kinthada shortlisted metal complexes of quercetin TSC and quercetin 3-O-glucoside Copper(II) compounds and examined their anti-proliferative and apoptosis activity on numerous cancer cell lines.…”