Kittler L, Wähnert U, Baguley B C, Bailly C, Waring M J, Löber G
Institut für Molekulare Biotechnologie e.V., Jena, Germany.
Anticancer Drug Des. 1996 Mar;11(2):101-15.
Ten bisquaternary ammonium heterocycles (BQA) active against experimental tumours were investigated for possible sequence-selective binding to DNA. Footprinting analyses indicated that several bound preferentially to dAdT runs consisting of at least four base pairs. Shortening of one or two spacer groups between the aromatic rings of the ligands (by replacement of CONH with NH) emerged as a prerequisite for sequence-specific binding. Other relevant factors concerned the overall shape of the ligands and the relative position of their positive charges. Footprinting plots evaluated for the BQA compound SN 6132 on the 167mer EcoRI-RsaI restriction fragment from plasmid pBR322 yielded the highest individual binding constant for the symmetrical base sequence AATTTAA, with approximate K(A) = 2.0 x 10(6)/M. Polymerase-catalysed syntheses of DNA and RNA in vitro were inhibited by all BQA derivatives, but the inhibition was much more pronounced with the sequence-specific binders SN 6999 and SN 6132 than with the non-specific ligand SN 6113.
研究了十种对实验性肿瘤有活性的双季铵盐杂环化合物（BQA）与DNA可能的序列选择性结合情况。足迹分析表明，有几种化合物优先结合至少由四个碱基对组成的dAdT序列。配体芳环之间一个或两个间隔基团的缩短（用NH取代CONH）是序列特异性结合的前提条件。其他相关因素涉及配体的整体形状及其正电荷的相对位置。对来自质粒pBR322的167聚体EcoRI-RsaI限制片段上的BQA化合物SN 6132进行足迹分析，得出对称碱基序列AATTTAA的个体结合常数最高，约K(A)=2.0×10(6)/M。所有BQA衍生物均抑制体外DNA和RNA的聚合酶催化合成，但序列特异性结合剂SN 6999和SN 6132的抑制作用比非特异性配体SN 6113更为明显。
