Biological evaluation of bis(indolyl)methane derivatives as Bcl-2 inhibitor in HL-60 cells Nadrahtul Huda Misral 1 , Siti Aishah Hasbullah 2 1 Pusat Tamhidi Universiti Sains Islam Malaysia, Malaysia, 2 Centre of Advanced Materials and Renewable Resources, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Malaysia Indole has shown remarkable anticancer activities which resulted to exploration of compounds containing indole unit. Bis-indolylmethanes bearing with two indole molecules were synthesized in a one pot reaction and their antiproliferative activity against HL-60 cell were evaluated in the present work. Our finding suggests that all synthesized bis-indolylmethanes, moderately inhibited the proliferation of HL-60 cell at a concentration of 50 µM except for ligands 4 and 7 which having slightly higher activity and been selected as the best ligands for continuation of further biological and computational study. Both of the ligands ( 4 and 7 ) having significant functional group at good positions (ligand 4 has methoxy group at 3,4,5 positions in benzene ring and ligand 7 has acetamido group at para position in benzene ring) which demonstrated best potency of inhibition activity at final concentration of 100 µM with IC 50 values of 44.4 and 62.63 µM respectively. Morphological observation revealed numerous disintegrated nuclei which signified apoptosis. In addition, UV-vis titration with ctDNA indicated the anticancer properties of bis-indolylmethanes which has been ascribed to its capability in binding to DNA and leading to cancer cell death with the binding constant value (K b ) for ligands 4 and 7 are 6.02×10 4 M −1 and 1.04×10 4 M −1 correspondingly. Molecular docking study displayed that bis-indolylmethanes 4 and 7 stably binds into the anti-apoptotic protein (Bcl-2) binding hot spot (P2 and P4) via interactions formed with Arg143, Asp108, Phe101, Phe109, Met112, Glu149, Phe150, Leu134, Glu133, Ala146, and Val153. Collectively, our works highlight the potential of undiscovered bis-indolylmethane derivatives as anticancer agents. References 1. Kalla, R. M. N., Hong, S. C. & Kim, I. Synthesis of Bis(indolyl)methanes Using Hyper-Cross-Linked Polyaromatic Spheres Decorated with Bromomethyl Groups as Efficient and Recyclable Catalysts. ACS Omega. 2018, 3, 2242–2253. 2. Sheryn, W., Ninomiya, M., Koketsu, M. & Hasbullah, S. A. In-vitro cytotoxicity of synthesized phthalide-fused indoles and indolines against HL-60 and HepG2 cells. Arab. J. Chem. 2020, 13, 3856–3865. 3. Liew, S. K., Malagobadan, S., Arshad, N. M. & Nagoor, N. H. A review of the structure—activity relationship of natural and synthetic antimetastatic compounds. Biomolecules. 2020, 10, 1–28. 4. Sani, N. D. M., Ariffin, E.Y., Sheryn, W., Shamsuddin, M.A., Heng, L.Y., Latip, J., Hasbullah, S.A. & Hassan,N.I. An electrochemical DNA biosensor for carcinogenicity of anticancer compounds based on competition between methylene blue and oligonucleotides. Sensors (Switzerland). 2019, 19. 5. Konwar, D. & Bora, U. Free radical triggered convenient synthesis of bis(indolyl)methane with potassium peroxodisulfate as catalyst. Chemistry Select. 2020, 5, 7460–7466.
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