1. Synthesis, characterization, and molecular structure of a novel zinc (II) complex: assessment of impact of MDR1Pgp expression on its cytotoxic activity.
- Author
-
Harpstrite SE, Prior JL, Sivapackiam J, Collins SD, Rath NP, and Sharma V
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Survival drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Humans, Models, Molecular, Molecular Structure, Organometallic Compounds chemical synthesis, Organometallic Compounds chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Agents pharmacology, Organometallic Compounds pharmacology, Zinc chemistry
- Abstract
Zinc(II)complex (3) {bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3-aminopropyl)ethylenediamine}-zinc(II); [(3-OEt-ENBDMPI)Zn(II)] was obtained in situ by a ligand exchange reaction involving zinc(II) acetylacetonate and the Schiff-base ligand obtained in situ. For assessing ability of 3 to act as a transport substrate of multidrug resistance (MDR1) P-glycoprotein (Pgp), its cytotoxic activity was evaluated in human epidermal carcinoma drug-sensitive KB 3-1 (Pgp-) and drug resistant KB 8-5 (Pgp+) cells. Compared with its cationic gallium(III) counterpart 4 showing cytotoxicity profiles consistent with its recognition as a Pgp substrate, the neutral zinc(II) complex 3 did not display cytotoxicity profiles (at pharmacologically relevant concentrations <10 µM) modified by expression of Pgp. Further, 3 was found be slightly more toxic against KB 8-5 cells compared to KB 3-1 cells at higher concentration. The neutral zinc (II) complex 3 was also found to be considerably less toxic against Pgp-lacking cells compared to its cationic gallium(III) counterpart 4. Additionally, the neutral zinc(II) complex 3 demonstrated considerably more toxicity against Pgp expressing KB 8-5 cells (> 10 µM) compared with its cationic counterpart 4 displaying minimal effect at highest concentration. The results suggest that differential cytotoxic activity of 3 and 4 in drug-resistant human epidermal carcinoma KB 8-5 (Pgp+) cells could result from variation in the overall charge of the molecules.
- Published
- 2010
- Full Text
- View/download PDF