Guanidino Anthrathiophenediones as G‑Quadruplex Binders: Uptake, Intracellular Localization, and Anti-Harvey-ras Gene Activity in Bladder Cancer Cells

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 express...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2013-04, Vol.56 (7), p.2764-2778
Main Authors: Cogoi, Susanna, Shchekotikhin, Andrey E, Membrino, Alexandro, Sinkevich, Yuri B, Xodo, Luigi E
Format: Article
Language:English
Subjects:
Animals
Cell Division
Cell Line, Tumor
Endocytosis
Flow Cytometry
G-Quadruplexes
Genes, ras
Humans
Mice
NIH 3T3 Cells
Thiophenes - pharmacology
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - metabolism
Urinary Bladder Neoplasms - pathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm3019063