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Photoswitchable DNA-Intercalators for targeted regulation of transcription

用于转录定向调控的光开关 DNA 嵌入剂

基本信息

批准号：
255999580
负责人：
Professor Dr. Heiko Ihmels
金额：
--
依托单位：
Fakultät für Chemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/255999580?language=en
关键词：
Photoswitchable DNA Intercalators targeted regulation

项目摘要

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.

光致变色化合物在化学和生物化学识别过程的外部刺激方面显示出很高的潜力。利用不同的分子光开关(偶氮苯、二芳基乙烯、螺吡喃/恶嗪)合成可光开关插层剂，并根据它们与DNA的相互作用对其结构和功能进行表征。双环去脂肽Triostin A，特别是其相关串联被认为是将被光开关基团修饰的原型靶标。DNA双嵌入剂Triostin A和Tandem属于喹恶啉类抗生素家族。这两个喹恶啉部分跨酰胺键结合到含有D-丝氨酸、L-丙氨酸、N-甲基-L-半胱氨酸和N-甲基-L-缬氨酸的双环八肽上，两个半胱氨酸残基之间有二硫键。Tandem不含任何N-甲基氨基酸。Triostin A显示出对革兰氏阳性细菌的抗生素活性，这是由于喹恶啉残基插入DNA的小凹槽而引起的。这导致了DNA阻断DNA-和RNA-聚合酶的结构变化。在自己的初步实验中，偶氮桥联的串联衍生物被证明是有趣的双稳开关，在黑暗中从顺式构型到反式构型的异构化非常缓慢。因此，这种串联衍生物将在几何上进行优化，除了改善水溶性外，还可以显示更好的与DNA的结合性能。根据获得光开关插层剂的不同策略，串联衍生物中的喹恶啉部分将被能够以花菁形式存在时能够插入的光开关螺吡喃和螺恶嗪所取代。此外，DNA结合的杂环聚酰胺将与可光切换的螺吡喃偶联。这些修饰将允许通过外部刺激(光)影响与DNA结合的能力。光化学转换将允许在体外或在一个细胞群体内同步生化过程、复制和转录，并触发或控制它们。