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Isomeric Effect on the Pharmacokinetic Behavior of Anticancer Cu II Mixed Chelate Complexes: Experimental and Theoretical Approach
Author(s) -
GarcíaRamos Juan Carlos,
VértizSerrano Guadalupe,
MacíasRosales Lucia,
GalindoMurillo Rodrigo,
ToledanoMagaña Yanis,
Bernal Juan Pablo,
CortésGuzmán Fernando,
RuizAzuara Lena
Publication year - 2017
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201601199
Subject(s) - chemistry , intermolecular force , membrane , chelation , molecule , phenanthroline , hydrogen bond , pharmacokinetics , cytotoxicity , stereochemistry , crystallography , organic chemistry , in vitro , biochemistry , bioinformatics , biology
We present herein the results of a pharmacokinetic (PK) study of Cu II mixed‐chelate coordination compound CasIII‐La {[Cu(5,6‐dimethyl‐1,10‐phenanthroline)(acetylacetonate)(H 2 O)]NO 3 }, which belongs to the antineoplastic family of compounds known as Casiopeínas. The main interest in this molecule lies in the big difference in its lethal dose and PK parameters in Wistar rats compared with its structural isomer CasIII‐Ea {[Cu(4,7‐dimethyl‐1,10‐phenanthroline)(acetylacetonate)(H 2 O)]NO 3 }. For instance, the half‐lives of these compounds are 9.6 ± 1.15 and 48 ± 4.6 h for CasIII‐La and CasIII‐Ea , respectively. The differences in the half‐lives have been attributed to their different capacities to cross cellular membranes. Molecular dynamics studies of a fraction of a cell membrane and Casiopeínas were developed to identify the possible intermolecular interactions responsible for the retention of the compound inside the cellular membrane. Also, quantum theory of atoms‐in‐molecules studies was developed to determine the capacity of the hydrogen atoms of methyl groups to participate in intermolecular interactions. In addition, peripheral human blood lymphocyte and macrophage samples were used to determine the cross‐membrane effect on cytotoxicity.