Abstract
Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.
Highlights
The aryl hydrocarbon receptor (AhR) is a cytosolic regulatory protein of the Per–AhR nuclear transporter (ARNT)–Sim (PAS) protein family, and can be stimulated by several endogenous and exogenous ligands
Some of molecules synthesized in this study demonstrated notable therapeutic efficacy exclusively in the lung and prostate cancer cell line with IC50 values up to 2.32 ± 0.11 and 9.92 ± 0.13 μM, respectively
This study describes the synthesis of a novel series of molecules designed in purview of the therapeutic properties of indole scaffold, incorporating a pyrazoline nucleus with the assumption of a possible interaction with an aryl hydrocarbon receptor for enhanced chemotherapeutic effects
Summary
The aryl hydrocarbon receptor (AhR) is a cytosolic regulatory protein of the Per–ARNT–Sim (PAS) protein family, and can be stimulated by several endogenous and exogenous ligands. The AhR, in the absence of a ligand, is present in the cytoplasm as a tetrameric chaperone complex, which includes the dimer of Hsp, p23, immunophilin-like. Ligands binding to the complex induces structural changes, which in turn results in the dissociation of the chaperone complex, exposing the nuclear localization sequence which enables its translocation towards the nucleus along with the ligand [4,5]. The AhR nuclear transporter (ARNT) association promotes the formation of the high-affinity DNA-binding complex, a complex of heterodimeric transcription factor [6]. The formation of the AhR/ARNT heterodimer enables it to bind to the DNA replication-related element (DRE) of the DNA sequence, which in turn leads to the remodeling of the chromatin network triggering transcription of downstream genes [7,8,9]. The AhR has been reported to regulate various biological pathways, and play a major role in the maintenance of normal cellular functions, which includes maintaining intestinal homeostasis, epithelial barrier function, host immune function & regulation, epidermal formation, organogenesis, cell migration, cell cycle, and proliferation [10,11,12,13,14]
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