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 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 ‘<i>cis</i>-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 <i>P-1</i>. 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 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. Mn(phen)<sub>2</sub>Cl<sub>2</sub> demonstrated significant anticancer potential against HeLa and MCF-7 cancer cells and less toxic behaviour towards normal BHK-21 cells. Fluorescence imaging confirmed that the production of reactive oxygen species (ROS) in HeLa cells by Mn(phen)<sub>2</sub>Cl<sub>2</sub> induces oxidized fluorescence of dichlorofluorescein 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 and 4′,6-diamidino-2-phenylindole 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 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 fold and 4.8 fold 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 Δ<i>G</i> = −14.62 kJ/mol. Communicated by Ramaswamy H. Sarma