Systematic further development of caged prodrugs of protein kinase inhibitors by UV light and beta-irradiation

通过紫外光和 β 辐射系统地进一步开发蛋白激酶抑制剂的笼状前药

• 批准号: 242412745
• 负责人: Professor Dr. Christian Peifer
• 金额: --
• 依托单位: Abteilung Pharmazeutische und Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/242412745?language=en
• 关键词: Systematic; further; development; caged; prodrugs

The main objectives of the present application consist in a systematic further development and more detailed characterization of photo- and by beta-irrradiation activatable (so-called "caged") prodrugs of protein kinase inhibitors. On the basis of the established photo-pharmaceutical infrastructure and by our exciting results of the first application period we will continue to build a powerful medicinal-chemistry platform for caged prodrugs. Our approach will involve suitable scaffolds and kinase inhibitors for the photo- or by beta-irradiation activatable concept. Innovative applications for the control of drug release, optimization of inhibitor selectivity and efficacy, reduction of side effects and effective pharmacological tools can thus be developed. Activation of caged prodrugs by light showing a wavelength in the bio-optical window and in particular by beta-irradiation would enhance the tissue penetration thus providing significant therapeutic advantages. Using our knowledge it will then also be possible to develop caged inhibitors in the sense of a de novo design approach towards inhibitors of further kinase targets and beyond. Moreover, our results will be applicable to the photochemistry of protecting groups in particular for N-heterocycles.

本申请的主要目的在于系统地进一步开发和更详细地表征蛋白激酶抑制剂的光辐射和β-环糊精辐射可活化的（所谓的“笼状”）前药。在已建立的光制药基础设施的基础上，并通过我们第一个应用阶段的令人兴奋的结果，我们将继续为笼状前药建立一个强大的药物化学平台。我们的方法将涉及合适的支架和激酶抑制剂的光-或β-辐射激活的概念。因此，可以开发用于控制药物释放、优化抑制剂选择性和功效、减少副作用和有效药理学工具的创新应用。通过显示生物光学窗口中的波长的光，特别是通过β-照射活化笼状前药将增强组织穿透，从而提供显著的治疗优势。利用我们的知识，然后也将有可能开发笼状抑制剂的意义上的从头设计方法，对抑制剂的进一步激酶的目标和超越。此外，我们的研究结果将适用于光化学的保护基团，特别是对N-杂环。

项目成果

2-Azo-, 2-diazocine-thiazols and 2-azo-imidazoles as photoswitchable kinase inhibitors: limitations and pitfalls of the photoswitchable inhibitor approach

• DOI: 10.1039/c9pp00010k
• 发表时间: 2019-06-01
• 期刊: PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES
• 影响因子: 3.1
• 作者: Schehr, Miriam;Ianes, Chiara;Herges, Rainer
• 通讯作者: Herges, Rainer

Restricted suitability of BODIPY for caging in biological applications based on singlet oxygen generation

• DOI: 10.1039/d0pp00097c
• 发表时间: 2020-08
• 期刊: Photochemical & Photobiological Sciences
• 影响因子: 3.1
• 作者: Theo Rodat;Melanie Krebs;Alexander Döbber;B. Jansen;A. Steffen-Heins;K. Schwarz;C. Peifer