Gresh N, René B, Hui X W, Barsi M C, Roques B P, Garbay C
Laboratoire de Biochimie Théorique, Institut de Biologie-Physico-Chimique, Paris, France.
J Biomol Struct Dyn. 1994 Aug;12(1):091-110.
In order to target the major groove of DNA, we have designed novel peptide derivatives of 7-H pyridocarbazole, which is the chromophoric ring of ditercalinium, a potent antitumor bisintercalator. We will present here the results obtained with a compound that has a D-Asn tethered to the pyridinium nitrogen of the ring by a protonated beta-alanyl-ethyl chain. We have investigated two alternative means of intercalation of the chromophore: first, into the (pyrpur) sequences, d(CpG)2 and d(CpA).d(TpG); second, into the (pur-pyr) sequences, d(GpC)2 and d(GpT).d(ApC). For the first intercalative mode, the best bound triplet sequences are d(ACG).d(CGT) and d(ACA)d(TGT), namely with an adenine immediately upstream from the intercalation site. In these complexes, the chromophore has its concave side in the major groove, its long axis nearly colinear with the mean long axis of the two base pairs of the intercalation site, and a bidentate H-bonded configuration occurs which involves the C = O and NH groups of the D-Asn side chain and HN6 and N7 (resp.) of the adenine base upstream. One alkylammonium proton is H-bonded to N7 of the guanine of the intercalation site, on the strand opposite to the one bearing the adenine. In the second intercalative mode, the chromophore's concave site now faces one DNA strand, and both alkylammonium protons are involved in H-bonds with N7 and O6 of the 3' guanine on the same strand. The peptide's complexes with sequences having A, G, or C upstream of this guanine were computed to be energetically competitive with those with the best (pyr-pur) triplets. This provides a rare example of energetically favourable drug intercalation in-between (pur-pyr) sequences as compared to the standard (pyr-pur) ones. The synthesis of this compound was performed, and a series of footprinting experiments undertaken on a total of approximately 300 nucleotides. These experiments were consistent with the inferences from the theoretical computations.
为了靶向DNA的大沟，我们设计了7-H吡啶并咔唑的新型肽衍生物，7-H吡啶并咔唑是双特卡林（一种有效的抗肿瘤双嵌入剂）的发色环。我们将在此展示一种化合物的实验结果，该化合物通过质子化的β-丙氨酰-乙基链将D-天冬酰胺连接到环的吡啶鎓氮上。我们研究了发色团的两种嵌入方式：第一种是嵌入（嘧啶-嘌呤）序列，即d(CpG)2和d(CpA).d(TpG)；第二种是嵌入（嘌呤-嘧啶）序列，即d(GpC)2和d(GpT).d(ApC)。对于第一种嵌入模式，结合效果最佳的三联体序列是d(ACG).d(CGT)和d(ACA)d(TGT)，即在嵌入位点紧邻上游有一个腺嘌呤。在这些复合物中，发色团的凹面朝向大沟，其长轴几乎与嵌入位点的两个碱基对的平均长轴共线，并且发生了双齿氢键构型，涉及D-天冬酰胺侧链的C=O和NH基团以及上游腺嘌呤碱基的HN6和N7（分别）。一个烷基铵质子与嵌入位点鸟嘌呤的N7形成氢键，位于与带有腺嘌呤的链相对的链上。在第二种嵌入模式中，发色团的凹面现在面向一条DNA链，并且两个烷基铵质子都参与与同一条链上3'端鸟嘌呤的N7和O6形成氢键。计算得出，该肽与在该鸟嘌呤上游具有A、G或C的序列形成的复合物在能量上与与最佳（嘌呤-嘧啶）三联体形成的复合物具有竞争力。与标准的（嘌呤-嘧啶）序列相比，这提供了一个在（嘧啶-嘌呤）序列之间进行能量上有利的药物嵌入的罕见例子。我们进行了该化合物的合成，并对总共约300个核苷酸进行了一系列足迹实验。这些实验与理论计算得出的推论一致。
