Strekowski L, Chandrasekaran S, Wang Y H, Edwards W D, Wilson W D
J Med Chem. 1986 Jul;29(7):1311-5. doi: 10.1021/jm00157a037.
The interaction of two phleomycin amplifiers, N,N-dimethyl-2-[[4'-(thien-2''-yl)pyrimidin-2'-yl]thio]ethylamine (1S, high activity) and N-[2''-(dimethylamino)ethyl]-4-(thien-2'-yl)pyrimidin-2-amine (1N, low activity) with DNA has been evaluated. The visible absorption bands of both compounds shift to longer wavelengths, and both exhibit hypochromicity on titration with DNA. The effects for 1S at low concentration are significantly greater than for 1N. 1S increases the DNA Tm by 2.5 degrees C while 1N causes only a 1.0 degree C increase under the same conditions. Spectrophotometric binding analysis of the interaction of 1S and 1N with calf thymus DNA indicates that 1S binds over 4 times more strongly to this DNA than 1N. Both compounds increase DNA viscosity, cause downfield shifts in DNA 31P NMR spectra, and shift the DNA imino base pair protons upfield, conclusively demonstrating that they bind to DNA by intercalation. Signals for the aromatic protons of 1S and 1N are shifted upfield on addition of DNA as expected for intercalation. The shifts for all aromatic protons are similar on 1S and on 1N, indicating that both the pyrimidine and thiophene are inserted between the DNA base pairs in the complex. NOE experiments demonstrate that the compounds are in the s-cis conformation both free in solution and in the DNA intercalation complex. Semiempirical INDO/S calculations indicate greater polarization of the pi-electron system of 1S than 1N. This greater polarization may account for the stronger interaction of 1S with DNA base pairs than 1N. The interaction of these compounds with DNA is strongly correlated with their biological amplification activity.
已对两种博来霉素增效剂，即N,N-二甲基-2-[[4'-(噻吩-2''-基)嘧啶-2'-基]硫代]乙胺（1S，高活性）和N-[2''-(二甲基氨基)乙基]-4-(噻吩-2'-基)嘧啶-2-胺（1N，低活性）与DNA的相互作用进行了评估。两种化合物的可见吸收带均向更长波长移动，并且在用DNA滴定过程中均表现出减色效应。低浓度下1S的效应明显大于1N。在相同条件下，1S使DNA的熔点（Tm）升高2.5℃，而1N仅使熔点升高1.0℃。对1S和1N与小牛胸腺DNA相互作用的分光光度结合分析表明，1S与该DNA的结合强度比1N强4倍以上。两种化合物均增加DNA粘度，导致DNA 31P NMR谱中的信号向低场移动，并使DNA亚氨基碱基对质子向高场移动，最终证明它们通过嵌入作用与DNA结合。加入DNA后，1S和1N的芳族质子信号如预期的嵌入作用那样向高场移动。1S和1N上所有芳族质子的位移相似，表明嘧啶和噻吩均插入复合物中的DNA碱基对之间。核Overhauser效应（NOE）实验表明，这些化合物在溶液中游离以及在DNA嵌入复合物中均处于s-顺式构象。半经验的间略微分重叠/自洽场（INDO/S）计算表明，1S的π电子体系比1N具有更大的极化作用。这种更大的极化作用可能解释了1S与DNA碱基对比1N具有更强的相互作用。这些化合物与DNA的相互作用与其生物学扩增活性密切相关。
