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

[ Vol. 6 , Issue. 4 ]


Scott E. Harpstrite, Julie L. Prior, Jothilingam Sivapackiam, Silvia D. Collins, Nigam P. Rath and Vijay Sharma   Pages 191 - 199 ( 9 )


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.


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


Mallinckrodt Institute of Radiology, BRIGHT Institute, Molecular Imaging Center, Washington University School of Medicine, Box 8225, 510 S. Kingshighway Blvd., St.Louis, MO 63110.

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