Synthesis, aqueous reactivity, and biological evaluation of carboxylic acid ester-functionalized platinum-acridine hybrid anticancer agents.

Abstract

The synthesis of platinum-acridine hybrid agents containing carboxylic acid ester groups is described. The most active derivatives and the unmodified parent compounds showed up to 6-fold higher activity in ovarian cancer (OVCAR-3) and breast cancer (MCF-7, MDA-MB-231) cell lines than cisplatin. Inhibition of cell proliferation at nanomolar concentrations was observed in pancreatic (PANC-1) and nonsmall cell lung cancer cells (NSCLC, NCI-H460) of 80- and 150-fold, respectively. Introduction of the ester groups did not affect the cytotoxic properties of the hybrids, which form the same monofunctional-intercalative DNA adducts as the parent compounds, as demonstrated in a plasmid unwinding assay. In-line high-performance liquid chromatography and electrospray mass spectrometry (LC-ESMS) shows that the ester moieties undergo platinum-mediated hydrolysis in a chloride concentration-dependent manner to form carboxylate chelates. Potential applications of the chloride-sensitive ester hydrolysis as a self-immolative release mechanism for tumor-selective delivery of platinum-acridines are discussed.

• Authors: Leigh A Graham, Jimmy Suryadi, Tiffany K West, Gregory L Kucera, Ulrich Bierbach
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 17 Pg. 7817-27 (Sep 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22871158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carboxylic Acids
• Esters
• Water
• Platinum

Topics

• Carboxylic Acids (chemistry)
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Esters
• Humans
• Platinum (chemistry)
• Spectrometry, Mass, Electrospray Ionization
• Water