Controlling the reactivity of [Pd(II)(N^N^N)Cl]+ complexes using 2,6-bis(pyrazol-2-yl)pyridine ligands for biological application: Substitution reactivity, CT-DNA interactions and in vitro cytotoxicity study

Daniel O Onunga; Rajesh Bellam; Gershom K Mutua; Meshack Sitati; Manickam D BalaKumaran; Deogratius Jaganyi; Allen Mambanda

doi:10.1016/j.jinorgbio.2020.111261

Controlling the reactivity of [Pd^(II)(N^N^N)Cl]⁺ complexes using 2,6-bis(pyrazol-2-yl)pyridine ligands for biological application: Substitution reactivity, CT-DNA interactions and in vitro cytotoxicity study

J Inorg Biochem. 2020 Dec:213:111261. doi: 10.1016/j.jinorgbio.2020.111261. Epub 2020 Sep 29.

Authors

Daniel O Onunga¹, Rajesh Bellam², Gershom K Mutua³, Meshack Sitati⁴, Manickam D BalaKumaran⁵, Deogratius Jaganyi⁶, Allen Mambanda²

Affiliations

¹ School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209, South Africa; Department of Chemistry, Maseno University, P.O. Box 333-40105, Maseno, Kenya. Electronic address: donugake@yahoo.com.
² School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209, South Africa.
³ School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209, South Africa; Department of Pure and Applied Chemistry, Masinde Muliro University of Science and Technology, P.O. Box 190, Kakamega 50100, Kenya.
⁴ School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Scottsville, Pietermaritzburg 3209, South Africa; Department of Mathematics and Physical Sciences, Maasai Mara University, P.O. Box 861 Narok 20500, Kenya.
⁵ Department of Biotechnology, Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, Chennai 600106, Tamil Nadu, India.
⁶ School of Pure and Applied Sciences, Mount Kenya University, P.O. Box 342-01000, Thika, Kenya; Department of Chemistry, Durban University of Technology, P.O. Box 1334, Durban 4000, South Africa. Electronic address: deojaganyi@gmail.com.

PMID: 33011625
DOI: 10.1016/j.jinorgbio.2020.111261

Abstract

Four [(N^N^N)Pd^(II)Cl]⁺ complexes [chloride-(2,2':6',2''-terpyridine)Pd(II)]Cl (PdL1), [chlorido(2,6-bis(N-pyrazol-2-yl)pyridine)Pd(II)]Cl (PdL2), [chlorido(2,6-bis(3,5-dimethyl-N-pyrazol-2-yl)pyridine)Pd(II)]Cl (PdL3) and [chlorido(2,6-bis(3,5-dimethyl-N-pyrazol-2-ylmethyl)pyridine)Pd(II)]BF₄ (PdL4) were synthesized and characterized. The rates of substitution of these Pd(II) complexes with thiourea nucleophiles viz; thiourea (Tu), N,N'-dimethylthiourea (Dmtu) and N,N,N',N'-tetramethylthiourea (Tmtu) was investigated under pseudo first-order conditions as a function of nucleophile concentration [Nu] and temperature using the stopped-flow technique. The observed rate constants vary linearly with [Nu]; k_obs = k₂[Nu] and decreased in the order: PdL1 > PdL2 > PdL3 ≫ PdL4. The lower π-acceptability of the cis-coordinated N-pyrazol-2-yl groups (which coordinates via pyrazollic-N π-donor atoms) of the PdL2-4 significantly decelerates the reactivity relative to PdL1. Furthermore, the six-membered chelates having methylene bridge in PdL4 do not allow π-extension in the ligand and introduces steric hindrance further lowering the reactivity. Trends in DFT calculated data supported the observed reactivity trend. Spectrophotometric titration data of complexes with calf thymus DNA (CT-DNA) and viscosity measurements of the resultant mixtures suggested that associative interactions occur between the complexes and CT-DNA, likely through groove binding with high binding constants (K_b = 10⁴ M^-1). In vitro MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxic activity data showed that PdL1 was the most potent complex against MCF7 breast cancer cells; its IC₅₀ value is lower than that of cisplatin. The results demonstrate how modification of a spectator ligand can be used to slow down the reactivity of Pd(II) complexes. This is of special importance in controlling drug toxicity in both pharmaceutical and biomedical applications.

Keywords: Calf thymus DNA; Cytotoxicity; Kinetics; Pd(II) complexes; Pyrazollic-N π-donor; Thiourea.

Publication types

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

MeSH terms

Animals
Cattle
Cell Line, Tumor
Chlorocebus aethiops
Coordination Complexes / chemistry
Coordination Complexes / pharmacology*
Crystallography, X-Ray
DNA / drug effects*
Density Functional Theory
Drug Screening Assays, Antitumor
Humans
In Vitro Techniques
Kinetics
Ligands
Molecular Structure
Palladium / chemistry
Palladium / pharmacology*
Spectrum Analysis / methods
Thermodynamics
Vero Cells

Substances

Coordination Complexes
Ligands
Palladium
DNA