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Syntheses, Characterization of Imidazo[4,5-F][1,10]Phenanthroline Derivative and As (Iii) Complex, in Vitro Evaluation, the Determine of Apoptosis Mechanism; Theoretical and Quantum Studies Publisher



Iraji M1 ; Khaleghian A1, 3 ; Malekshah RE2 ; Abbasi M1 ; Basir D1
Authors
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Authors Affiliations
  1. 1. Biochemistry Department, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
  2. 2. Medical Biomaterial Research Centre (MBRC), Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran

Source: Journal of Drug Delivery Science and Technology Published:2023


Abstract

In the present work, a novel ligand, (4-amino-3-methoxybenzaldehyde)-1H-imidazo[4,5-f][1,10] phenanthroline (AMIP) based on the formation of an imidazole ring and [As(AMIP)](Cl)]Cl2 was synthesized and characterized through Fourier-transform infrared (FT-IR) spectroscopy. In addition, the anticancer activity of [As(AMIP)](Cl)]Cl2 complex was tested against human acute promyelocytic leukemia cells (HL-60) and granulocytic differentiation of human promyelocytic leukemia cells (NB4). The MTT results showed IC50 values of 7.31 ± 15 and 8.4 ± 62 μM for As (III) complex against NB4 and HL-60, respectively. In a study on both cell lines, As (III) reduced gene expression Bcl-2 and Bcl-xl, increased Bax and Bad, and activated caspase-3, resulting in apoptosis. The dye Hoechst 33342 showed increased apoptosis induction in the NB4 cell line than in the HL-60 cell line. BrdU test exhibited an inhibitory effect on DNA synthesis. The protein levels of caspase-3 were enhanced in a dose-dependent manner in both HL-60 and NB-4 cell lines. Based on the Annexin V-FITC/PI assay, apoptosis was the primary mechanism of cell death. The real-time polymerase chain reaction (real-time PCR) results demonstrated that the expression level of Atg 12, Atg 7, Lc 3, and Beclin-1 genes, antiapoptotic genes including Bcl-2 and Bcl-xl, and apoptotic genes containing BAD and BAX was improved. Furthermore, the hemolysis assay showed the anti-hemolytic activity of the complex. Moreover, quantum chemical calculations were utilized to optimize all structures, and the output results were employed to study molecular docking of compounds with caspase-3 tethered to irreversible inhibitor (PDB ID: 1NMS) and DNA with sequence d(CCGTCGACGG) (PDB ID:423D). The results showed that As (III) complex had the lowest-energy conformation, suggesting the optimal interaction. © 2023
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