The computer-aided QSAR calculations are commonly applied to rational designing of many group of drugs except of Pt-based agents. We present the results of seeking for the QSAR correlation between antiproliferative activity and molecular descriptors of Pt-drug analogs.

The main goal of this study was to complete Hansch equation [1] showing the relations between hydrophobicity (independent variable) and biological activity (dependent variable) in the series of neutral platinum(II) complexes. The object of these studies were two groups of dicarboxylate platinum complexes, one with primary N-donors (ethylenediamine), and the second with tertiary N-donors (1-alkylimidazole).

The hydrophobicity (log P) of the series of compounds was determined using a shake-flask method; the platinum content of the organic and aqueous phases was measured by ICP. The biological activity was expressed as 1/C, where C was the concentration of drug required to kill 50% of the treated cells. The cytotoxicity concentration (IC50) of platinum complexes was determined by SRB and MTT assays [2] on the human breast cancer (MCF-7) and leukemia (HL-60) cell lines.

As we found earlier [3] the studied complexes differed significantly in their crosslinking ability when they interacted with plasmid DNA. To find the reason of such behavior we evaluated the representative complexes on ovarian carcinoma OvBH-1 cells by immunohistochemical staining using monoclonal antibodies.

The results of SRB or MTT assays demonstrate that new platinum(II) complexes exhibit wide range of cytotoxicity (IC50), between 4.8 and 70.3 microg/ml. In general, they reveal higher antiproliferative activities than referential carboplatin against both cell lines, and the leukemia cells HL-60 are more sensitive target than MCF-7. The regression analyses based on Hansch equation indicate the correlation between the measured value of logP and cytotoxicity, expressed by log 1/C (for IC50). The results of immunohistochemical evaluation, which present the influence of platinum complexes on expression of multi-drug resistant proteins (P-gp, MRP, LRP), apoptosis related proteins (Bax, p53, Bcl-2) and mismatch repair gene product (hMLH1), showed the big differences in the action of platinum species. This is in agreement with differences at crosslinking DNA observed earlier by us on another way [3].

References

[1] Hansch C. and Fujita T., J. Am. Chem. Soc., 86, 1616 (1964).[2] Skehan P. et al.; J. Natl. Cancer Inst., 82, 1107 (1990).[3] Grądzka I., Buraczewska I., Kuduk-Jaworska J., Romaniewska A., Szumiel I., Chem.-Biol. Interact., 146, 165 (2003).

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2. DICARBOXYLATOPLATINUM(II) COMPLEX - SIX TIMES LESS TOXIC THAN CARBOPLATIN
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