Department of Medical and Biological Science, Ple Kolbe 4, School of Medicine, 33100 Udine, Italy.
J Med Chem. 2013 Apr 11;56(7):2764-78. doi: 10.1021/jm3019063. Epub 2013 Mar 21.
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.
我们制备了一系列带有不同长度胍基烷基侧链的蒽并噻吩二酮（ATPDs）（化合物 1、10-13）。目的是研究它们与 DNA 和 RNA G-四链体的相互作用、在恶性和非恶性细胞中的摄取以及它们调节基因表达和抑制细胞生长的能力。流式细胞术显示，这些 ATPDs 更有效地进入恶性 T24 膀胱细胞，而非恶性胚胎肾 293 或成纤维细胞 NIH 3T3 细胞。在 T24 恶性细胞中，带有两个乙基侧链的化合物 1 通过内吞作用被摄取，而带有分别带有丙基和丁基侧链的 12 和 13 则通过被动扩散进行运输。设计的 ATPDs 定位于细胞质和细胞核内，并与 DNA 和 RNA G-四链体紧密结合。它们还降低了 HRAS 的表达，增加了 G0/G1 期的细胞群，并强烈抑制了恶性 T24 膀胱细胞的增殖，但对非恶性 293 或 NIH 3T3 细胞没有影响。
