Synthesis, Characterization, and Molecular Structure of a Novel Zinc (II) Complex: Assessment of Impact of MDR1Pgp Expression on its Cytotoxic Activity

Scott      E. Harpstrite; Julie      L. Prior; Jothilingam      Sivapackiam; Silvia      D. Collins; Nigam      P. Rath; Vijay      Sharma

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.

Keywords: Metalloprobes, Zinc(II) complex, P-glycoprotein, Blood-Brain Barrier (BBB), Zinc (II) Complex, MDR1Pgp Expression, Schiff-base ligand, multidrug resistance, human epidermal carcinoma, Blood-Brain Barrier, polymerase chain reaction, immunohistochemistry, Alzheimer's, single photon emission com-puted tomography, 99mTc-Sestamibi, 99mTc-furifosmin, 99mTc-Q58, 99mTc-COMIBI, positron emission tomography, toluene, aldimino protons, aromatic protons, X-ray crystallography, Zn-3-OEt-ENDMPI, phosphate buffered saline, cysteine, HPLC, DMSO, LC50 values, Ga-3-OEt-ENBDMPI, Pgp expressing drug-resistant KB, cytotoxicity, Pgp expressing cells, zinc(II) nitrate, Metal nitrates, spectrometer, Bioorganic Mass Spectrometry, potassium hydroxide, Detector, human epidermoid carcinoma