Binding mode transformation and biological activity on the Ru(II)-DMSO complexes bearing heterocyclic pyrazolyl ligands

Dorothy Priyanka Dorairaj; Ya-Fan Lin; Jebiti Haribabu; Theetharappan Murugan; Manmath Narwane; Ramasamy Karvembu; Mallanpillai Ananthakrishnan Neelakantan; Chai-Lin Kao; Chien-Chih Chiu; Sodio C N Hsu

doi:10.1016/j.jinorgbio.2021.111545

Binding mode transformation and biological activity on the Ru(II)-DMSO complexes bearing heterocyclic pyrazolyl ligands

J Inorg Biochem. 2021 Oct:223:111545. doi: 10.1016/j.jinorgbio.2021.111545. Epub 2021 Jul 16.

Affiliations

¹ Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research Centre, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India.
² Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research Centre, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Chemistry Research Centre, National Engineering College, K.R. Nagar, Kovilpatti, 628503 Thoothukudi District, Tamilnadu, India.
⁴ Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research Centre, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India.
⁶ Department of Medical Research, Kaohsiung Medical University Hospital, Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Electronic address: cchiu@kmu.edu.tw.
⁷ Department of Medicinal and Applied Chemistry, Drug Development and Value Creation Research Centre, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Electronic address: sodiohsu@kmu.edu.tw.

PMID: 34303108
DOI: 10.1016/j.jinorgbio.2021.111545

Abstract

Three Ru(II)-DMSO complexes (1-3) containing 2-(3-pyrazolyl)pyridine (PzPy), 2-pyrazol-3-ylfuran (PzO), or 2-pyrazol-3-ylthiophene (PzS) ligand, were synthesized and characterized. The monodentate coordination of the heterocyclic pyrazolyl ligand (Pz^Py) with Ru(II) ion via N atom was confirmed by single crystal X-ray diffraction. Complex 1 could be converted to the known η²-bidentate Pz^Py complex cis(Cl), cis(S)-[RuCl₂(Pz^Py)(DMSO)₂] (4) under reflux conditions. The mechanism underlying binding mode transformation was studied by ¹H NMR spectroscopy and density functional theory (DFT) calculations. The binding abilities of the complexes (1-4) with calf-thymus (CT) DNA and bovine serum albumin (BSA) were investigated using spectroscopic and molecular docking techniques. Among the four Ru(II) complexes, complexes 1 and 3 inhibited the long-term proliferation of human breast cancer cells, whereas complexes 2 and 4 did not inhibit their proliferation to a considerable extent. Interestingly, complexes 1 and 3 did not induce significant cell death but rather attenuated the clonogenicity of breast cancer cells by upregulating reactive oxygen species (ROS), endoplasmic reticulum (ER) and autophagic stress.

Keywords: Biomolecular interactions; Density functional theory; MDA-MB-231; Pyrazolyl ligands; ROS studies; Ruthenium-DMSO.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Cattle
Cell Line, Tumor
Coordination Complexes / chemical synthesis
Coordination Complexes / metabolism
Coordination Complexes / pharmacology*
DNA / metabolism
Dimethyl Sulfoxide / analogs & derivatives*
Dimethyl Sulfoxide / metabolism
Dimethyl Sulfoxide / pharmacology*
Drug Screening Assays, Antitumor
Humans
Ligands
Molecular Docking Simulation
Protein Binding
Pyrazoles / chemical synthesis
Pyrazoles / metabolism
Pyrazoles / pharmacology*
Reactive Oxygen Species / metabolism
Ruthenium / chemistry
Serum Albumin, Bovine / metabolism

Substances

Antineoplastic Agents
Coordination Complexes
Ligands
Pyrazoles
Reactive Oxygen Species
Serum Albumin, Bovine
Ruthenium
DNA
calf thymus DNA
Dimethyl Sulfoxide