Agbandje M, Jenkins T C, McKenna R, Reszka A P, Neidle S
Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
J Med Chem. 1992 Apr 17;35(8):1418-29. doi: 10.1021/jm00086a010.
A series of 2,6-bis(omega-aminoalkanamido)anthracene-9,10-diones (9,10-anthraquinones), of general formula Ar(NHCO(CH2)nNR2)2, where Ar = anthracene-9,10-dione and n = 1 or 2, have been synthesized by treatment of the corresponding bis(omega-haloalkanamido) derivatives with appropriate secondary amines. The DNA-binding properties of these compounds were evaluated by thermal denaturation studies, unwinding of closed-circular DNA, determination of association constants in solution, and examined by molecular modeling. A representative compound in the series has been examined by X-ray crystallography. In vitro cytotoxicity data is reported for the compounds and some indications of structure-activity relationships have been discerned. In particular, those compounds with two methylene links (n = 2) in each side chain separating the amide and terminal amine moieties have superior activity and, in general, enhanced DNA binding characteristics. It is postulated that the mode of reversible binding of these compounds to DNA involves the side chains occupying both major and minor grooves and, further, that this may confer cytotoxic properties which are distinct from those of previously reported anthracene-9,10-dione cytotoxins.
一系列通式为Ar(NHCO(CH2)nNR2)2的2,6 - 双（ω - 氨基链烷酰胺基）蒽 - 9,10 - 二酮（9,10 - 蒽醌）已通过相应的双（ω - 卤代链烷酰胺基）衍生物与适当的仲胺反应合成，其中Ar = 蒽 - 9,10 - 二酮，n = 1或2。通过热变性研究、闭环DNA解旋、溶液中缔合常数的测定对这些化合物的DNA结合特性进行了评估，并通过分子建模进行了研究。该系列中的一种代表性化合物已通过X射线晶体学进行了研究。报告了这些化合物的体外细胞毒性数据，并已识别出一些构效关系的迹象。特别地，在酰胺和末端胺部分之间的每个侧链中具有两个亚甲基连接（n = 2）的那些化合物具有优异的活性，并且总体上具有增强的DNA结合特性。据推测，这些化合物与DNA的可逆结合模式涉及侧链占据大沟和小沟两者，并且进一步地，这可能赋予与先前报道的蒽 - 9,10 - 二酮细胞毒素不同的细胞毒性特性。
