Mohammadi S, Perrée-Fauvet M, Gresh N, Hillairet K, Taillandier E
Laboratoire de Chimie Structurale et Spectroscopie Biomoléculaire (CNRS-URA 1430), Université Paris 13, Bobigny, France.
Biochemistry. 1998 Apr 28;37(17):6165-78. doi: 10.1021/bi972964h.
To target selectively the major groove of double-stranded B DNA, we have designed and synthesized a bis(arginyl) conjugate of a tricationic porphyrin (BAP). Its binding energies with a series of double-stranded dodecanucleotides, having in common a central d(CpG)2 intercalation site were compared. The theoretical results indicated a significant energy preference favoring major groove over minor groove binding and a preferential binding to a sequence encompassing the palindrome GGCGCC encountered in the Primary Binding Site of the HIV-1 retrovirus. Spectroscopic studies were carried out on the complexes of BAP with poly(dG-dC) and poly(dA-dT) and a series of oligonucleotide duplexes having either a GGCGCC, CCCGGG, or TACGTA sequence. The results of UV-visible and circular dichroism spectroscopies indicated that intercalation of the porphyrin takes place in poly(dG-dC) and all the oligonucleotides. Thermal denaturation studies showed that BAP increased significantly the melting temperature of the oligonucleotides having the GGCGCC sequence, whereas it produced only a negligible stabilization of sequences having CCCGGG or TACGTA in place of GGCGCC. This indicates a preferential binding of BAP to GGCGCC, fully consistent with the theoretical predictions. IR spectroscopy on d(GGCGCC)2 indicated that the guanine absorption bands, C6=O6 and N7-C8-H, were shifted by the binding of BAP, indicative of the interactions of the arginine arms in the major groove. Thus, the de novo designed compound BAP constitutes one of the very rare intercalators which, similar to the antitumor drugs mitoxantrone and ditercalinium, binds DNA in the major groove rather than in the minor groove.
为了选择性地靶向双链B-DNA的大沟，我们设计并合成了一种三阳离子卟啉的双（精氨酰）共轭物（BAP）。比较了它与一系列双链十二聚体核苷酸的结合能，这些核苷酸都有一个中心d（CpG）2嵌入位点。理论结果表明，与小沟结合相比，大沟结合具有显著的能量优势，并且优先结合包含HIV-1逆转录病毒主要结合位点中出现的回文序列GGCGCC的序列。对BAP与聚（dG-dC）、聚（dA-dT）以及一系列具有GGCGCC、CCCGGG或TACGTA序列的寡核苷酸双链体的复合物进行了光谱研究。紫外可见光谱和圆二色光谱的结果表明，卟啉在聚（dG-dC）和所有寡核苷酸中发生了嵌入。热变性研究表明，BAP显著提高了具有GGCGCC序列的寡核苷酸的解链温度，而对于用CCCGGG或TACGTA取代GGCGCC的序列，它只产生了可忽略不计的稳定性增强。这表明BAP优先与GGCGCC结合，与理论预测完全一致。对d（GGCGCC）2的红外光谱表明，鸟嘌呤吸收带C6=O6和N7-C8-H因BAP的结合而发生了位移，这表明精氨酸臂在大沟中发生了相互作用。因此，新设计的化合物BAP是非常罕见的嵌入剂之一，与抗肿瘤药物米托蒽醌和二萜卡林ium类似，它在大沟而非小沟中与DNA结合。
