Synthesis of 1-benzyl-1H-benzimidazoles as galectin-1 mediated anticancer agents |
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| Affiliation: | 1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India;2. Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500 046, India;3. Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India;1. Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, Andhra Pradesh, 522 510, India;2. Department of Chemistry, University College of Engineering (Autonomous), Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, 533003, India;3. Centre for Molecular Cancer Research, Vishnu Institute of Pharmaceutical Education & Research (VIPER), Narsapur, Medak, Telangana, 502313, India;4. Department of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh, 521 001, India |
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| Abstract: | In our pursuit to develop novel non-carbohydrate small molecule Galectin-1 Inhibitors, we have designed a series of 1-benzyl-1H-benzimidazole derivatives and demonstrated their anticancer activity. The compound 6g, 4-(1-benzyl-5-chloro-1H-benzo[d]imidazol-2-yl)-N-(4-hydroxyphenyl) benzamide was found to be most potent with an IC50 of 7.01 ± 0.20 µM and arresting MCF-7 cell growth at G2/M phase and S phase. Induction of apoptosis was confirmed by morphological changes like cell shrinkage, blebbing and cell wall deformation, dose dependent increase in the mitochondrial membrane potential (ΔΨm) and ROS levels. Further, dose dependent decrease in Gal-1 protein levels proves Gal-1 mediated apoptosis by 6g. Molecular docking studies were performed to understand the Gal-1 interaction with compound 6g. In addition, RP-HPLC studies showed 85.44% of 6g binding to Gal-1. Binding affinity studies by fluorescence spectroscopy and Surface Plasmon Resonance (SPR) showed that 6g binds to Gal-1 with binding constant (Ka) of 1.2 × 104 M−1 and equilibrium constant KD value of 5.76 × 10−4 M respectively. |
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| Keywords: | 1-benzyl-1H-benzimidazoles Galectin-1 Cancer Fluorescence spectroscopy RP-HPLC Surface plasmon resonance |
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