Anticancer evaluation of a Manganese Complex on HeLa and MCF-7 Cancer Cells: Design, Deterministic Solvothermal Synthesis Approach, Hirshfeld analysis, DNA Binding, Intracellular Reactive Oxygen Species (ROS) Production, Electrochemical Characterization and Density Functional Theory
Creators: name: Saghir Abbas
name: Rashid, Faisal
name: Ulker, Emine
name: Sumera Zaib
name: Ayub, Khurshid
name: Ullah, Sana
name: Nadeem, Muhammad Arif
name: Sammer Yousuf
name: Ludwig, Ralf
name: Ali, Saqib
name: Iqbal, Jamshed
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Molecular Biology
subject: Physiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Cancer
subject: Inorganic Chemistry

description: Herein, a deterministic solvothermal strategy was employed to synthesize an efficient anticancer agent “cis-dichlorobis(1,10-phenanthroline)manganese(II)” (Mn(phen)<sub>2</sub>Cl<sub>2</sub>). A single-crystal X-ray diffraction analysis revealed that Mn(phen)<sub>2</sub>Cl<sub>2</sub> crystallizes in a triclinic system with the space group P-1. Cyclic voltammetric studies of Mn(phen)<sub>2</sub>Cl<sub>2</sub> indicated that the electrode process occurs only due to complex formation and has a diffusion-controlled mechanism. Density functional theory (DFT) estimations showed that the Mn(phen)<sub>2</sub>Cl<sub>2</sub> is quite stable and exists in sextet spin state (five unpaired electrons) as the most stable form and hence, Mn(phen)<sub>2</sub>Cl<sub>2</sub> is a high spin complex. Compound Mn(phen)<sub>2</sub>Cl<sub>2</sub> demonstrated significant anticancer potential against HeLa and MCF-7 cancer cells and less toxic to normal BHK-21 cells. Fluorescence imaging confirmed that the production of H<sub>2</sub>O<sub>2</sub> in HeLa cells by Mn(phen)<sub>2</sub>Cl<sub>2</sub> induces oxidized fluorescence of dichlorofluorescein (DCF) which emitted fluorescence at 530 nm after excitation at 488 nm. The microscopic investigation of apoptotic effect of Mn(phen)<sub>2</sub>Cl<sub>2</sub> using propidium iodide (PI) and DAPI staining indicated that nuclear condensation, cell detachment and shrinkage occur after treatment with IC<sub>50</sub> values of Mn(phen)<sub>2</sub>Cl<sub>2</sub>. Furthermore, an assessment of caspase-9 and caspase-3 activity after exposure to compound Mn(phen)<sub>2</sub>Cl<sub>2</sub> in HeLa cells indicated that at IC<sub>50</sub> values of Mn(phen)<sub>2</sub>Cl<sub>2</sub>, 1.5 folds and 4.8 folds’ increase in caspase-9 and caspase-3 activity, respectively, occurs. The measurement of mitochondrial membrane potential of a cationic dye (JC-1) showed a decrease in mitochondrial membrane potential in both HeLa and MCF-7 cells depicting that compound might have adopted intrinsic pathway of apoptosis. Ability of Mn(phen)<sub>2</sub>Cl<sub>2</sub> to interact with HS-DNA demonstrates hyperchromicity with slight blue shift from 269 nm to 265 nm showing a non-covalent interaction with Gibbs free energy of ΔG = -14.62 kJ/mol.