Novel metal complex oligomer which forms triple helix with DNA

DNA三螺旋形成是控制基因表达和DNA复制的一种独特而有吸引力的方法。三螺旋是通过将单链DNA与双螺旋DNA结合而形成的。这与反义RNA/DNA的情况相反，后者需要单链核酸靶标。三螺旋结构具有高度的序列选择性，但它仅限于高嘌呤-高嘧啶序列的DNA。为了克服这一限制，我们研究了新型低聚物化合物，这些低聚物聚合后与一般碱基序列的双链DNA形成三螺旋。这种低聚单元可以是金属络合物，尽管在这种情况下在DNA沟槽中形成光滑的骨架可能是个问题。在这个项目中，我们设计了一种新的核苷酸类似物，它潜在地将一个特定的DNA碱基与其他DNA碱基区分开来，并可以整合到一个单链DNA中。在合成之前，通过计算机建模和力场计算来检查该化合物的序列识别能力。该化合物的合成正在进行中。此外，为了了解金属络合物在DNA沟槽中的结合模式，我们还研究了手性配体与铜的络合物。通过固有的DNA裂解能力来评估配体与DNA的结合。还发展了一种基于诱导CD光谱的获得金属卟啉与DNA结合的定量信息的方法。

DNA triple helix formation is a unique and an attractive approach towards the control of gene expression and DNA replication. Triple helices are formed by binding a single stranded DNA to a double helical DNA.This is in contrast to the case of antisense RNA/DNA which requires a single stranded nucleic acid target. Triple helix formation is highly sequence selective, however, it is limited to DNA of homopurine-homopyrimidine sequences. To overcome this limitation, we have investigated novel oligomer compounds which on polymerization form a triple helix with a double stranded DNA of general base sequence.Such oligomeric units can be metal complexes, although formation of a smooth backbone in the DNA groove may be problematic in this case. In this project we have designed a novel nucleotide analogue wihch potentially discriminates one particular DNA base from others and can be incorporated into a single stranded DNA.Prior to synthesis, the sequence recognizing ability of the compound was checked by computer modeling and force field calculations. Synthesis of the compound is underway. Additionally, to understand the binding mode of metal complexes in the DNA grooves, copper complexes with chiral ligands have been studied. Ligand binding to DNA was estimated through intrinsic DNA cleaving ability. A method for obtaining quantitative information on the binding of metalloporphyrins to DNA has also been developed based on induced CD spectroscopy.