Ohara Keiichiro, Smietana Michael, Restouin Audrey, Mollard Séverine, Borg Jean-Paul, Collette Yves, Vasseur Jean-Jacques
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UM I-UM II, Université de Montpellier II, France.
J Med Chem. 2007 Dec 27;50(26):6465-75. doi: 10.1021/jm701207m. Epub 2007 Dec 4.
A series of polyaromatic guanidino derivatives was synthesized and evaluated for growth inhibitory properties in several human carcinoma cell lines. The properties of these guanidino compounds were compared to those of their corresponding synthetic amino precursors. The size of the polyaromatic ring system as well as the length of the tether attached to the ring had a direct impact on the observed antiproliferative profiles, compound 14 having the broadest spectrum of activity. As both series intercalate DNA, guanidine derivatives showed a remarkable affinity for DNA and the guanidinium group appeared to be essential, yet not sufficient for caspase-3/7 activation. Compound 14 also showed significant in vivo activity against breast cancer cell xenografts in NOG/SCID mice. These results suggest that the electronic nature of chain tethering an intercalator not only influences the DNA-binding process but also controls the antitumoral activity of the whole compound.
合成了一系列多芳基胍衍生物，并在几种人类癌细胞系中评估了它们的生长抑制特性。将这些胍化合物的特性与其相应的合成氨基前体的特性进行了比较。多芳环系统的大小以及连接到环上的链的长度对观察到的抗增殖谱有直接影响，化合物14具有最广泛的活性谱。由于两个系列都能嵌入DNA，胍衍生物对DNA表现出显著的亲和力，并且胍基团似乎是必不可少的，但不足以激活caspase-3/7。化合物14在NOG/SCID小鼠体内对乳腺癌细胞异种移植也显示出显著活性。这些结果表明，连接嵌入剂的链的电子性质不仅影响DNA结合过程，还控制整个化合物的抗肿瘤活性。
