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J Med Chem. 2013 Apr 11;56(7):2764-78. doi: 10.1021/jm3019063. Epub 2013 Mar 21.

Guanidino anthrathiophenediones as G-quadruplex binders: uptake, intracellular localization, and anti-Harvey-Ras gene activity in bladder cancer cells.

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  • 1Department of Medical and Biological Science, Ple Kolbe 4, School of Medicine, 33100 Udine, Italy.


We prepared a series of anthrathiophenediones (ATPDs) with guanidino-alkyl side chains of different length (compounds 1, 10-13). The aim was to investigate their interaction with DNA and RNA G-quadruplexes, their uptake in malignant and nonmalignant cells, and their capacity to modulate gene expression and inhibit cell growth. Flow cytometry showed that the ATPDs enter more efficiently in malignant T24 bladder cells than in nonmalignant embryonic kidney 293 or fibroblast NIH 3T3 cells. In T24 malignant cells, compound 1, with two ethyl side chains, is taken up by endocytosis, while 12 and 13, with respectively propyl and butyl side chains, are transported by passive diffusion. The designed ATPDs localize in the cytoplasm and nucleus and tightly bind to DNA and RNA G-quadruplexes. They also decrease HRAS expression, increase the cell population in G0/G1, and strongly inhibit proliferation in malignant T24 bladder cells, but not in nonmalignant 293 or NIH 3T3 cells.

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