Photoswitchable DNA-Intercalators for targeted regulation of transcription

光致变色化合物在化学和生物化学的再生过程中表现出很高的外部刺激潜力。将采用不同的分子光开关（偶氮苯、二芳基乙烯、螺吡喃/-恶嗪）合成光开关嵌入剂，并就其与DNA的相互作用的结构和功能进行表征。双环缩肽triostin A和特别是其相关的TANDEM被认为是将被光开关基团修饰的原型靶标。DNA双嵌入剂曲骨菌素A和TANDEM属于喹喔啉抗生素家族。两个喹喔啉部分通过酰胺键与含有D-丝氨酸、L-丙氨酸、N-甲基-L-半胱氨酸和N-甲基-L-缬氨酸的双环八缩肽结合，两个Cys残基之间具有二硫键。TANDEM不含任何N-甲基氨基酸。Triostin A对革兰氏阳性菌显示出抗生素活性，这是由喹喔啉残基嵌入DNA小沟引起的。偶氮桥连的TANDEM衍生物在自己的初步实验中被证明是有趣的双链开关，在黑暗中从顺式到反式构型的异构化非常缓慢。因此，这种TANDEM衍生物将在几何上优化，以显示除了改善的水溶性之外，更好的与DNA的结合特性。根据获得光可切换嵌入剂的不同策略，TANDEM衍生物中的喹喔啉部分将被光可切换螺吡喃和螺恶嗪取代，当以汞形式存在时，所述螺吡喃和螺恶嗪能够嵌入。此外，DNA结合杂环聚酰胺将与光可转换螺吡喃缀合。这些修饰将允许通过外部刺激（光）影响与DNA结合的能力。光化学开关将允许同步生物化学过程复制和转录在体外或细胞群体内，并触发或控制它们。

Photochromic compounds display high potential for the external stimulation of chemical and biochemical regognition processes. Photoswitchable intercalators will be synthesized employing different molecular photoswitches (azobenzenes, diarylethenes, spiropyrans/-oxazins) and characterized with respect to structure and function regarding their interaction with DNA. The bicyclic depsipeptide triostin A and especially its correlate TANDEM are considered as prototype targets that will be modified by photoswitchable groups. The DNA- bisintercalators triostin A and TANDEM belong to the family of quinoxaline antibiotics. Both quinoxaline moieties are bound across an amide bond to a bicyclic octadepsipeptide containing D-serine, L-alanine, N-methyl-L-cystein, and N-methyl-L-valine, with a disulfide bond between the two Cys residues. TANDEM does not contain any N-methyl amino acids. Triostin A displays antibiotic activity against gram-positive bacteria that is caused by intercalation of the quinoxaline residues into the minor groove of DNA. This causes structural changes in DNA blocking DNA- and RNA-polymerase.Azo-bridged TANDEM derivatives were shown in own preliminary experiments to be interesting bistable switches that isomerize only very slowly in the dark from the cis- to the trans-configuration. Consequently, such TANDEM derivatives will be geometrically optimized to display, besides improved water solubility, better binding properties to DNA. According to a different strategy to obtain photoswitchable intercalators, the quinoxaline moieties in TANDEM derivatives will be replaced by photoswitchable spiropyrans and spirooxazins that are able to intercalate when present in the merocyanine form. In addition, DNA-binding heterocyclic polyamides will be conjugated with photoswitchable spiropyrans. These modifications will allow to influence the ability of binding to DNA by an external stimulus (light). Photochemical switching will allow to synchronize the biochemical processes replication and transcription in vitro or within a cell population and to trigger or control them.