Lützel Kyra, Laqua Henryk, Sathian Manjima B, Nißl Benedikt, Szántó Judit Katalin, Senser Christina-Anna, Savasci Gökcen, Allmendinger Lars, Kicin Bilal, Ruf Vincent, Kammerer Dominik, Lohmüller Theobald, Karaghiosoff Konstantin, Ali Ahmed M, Storch Ursula, Mederos Y Schnitzler Michael, Ochsenfeld Christian, Konrad David B
Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Munich, 81377, Germany.
Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Munich, 81377, Germany.
Angew Chem Int Ed Engl. 2025 Aug 4;64(32):e202501779. doi: 10.1002/anie.202501779. Epub 2025 Jun 23.
Azobenzenes are versatile photoswitches that can be used to generate elaborate optical tools, including photopharmaceuticals. However, the targeted application-guided design of new photoswitches with specific properties remains challenging. We have developed synthetic protocols for derivatives of the dfdc (di-ortho-fluoro-di-ortho-chloro) azobenzene scaffold with chemical alterations in the para-/ortho-positions and performed an in-depth study into the effects of their structures on their photophysical properties with an emphasis on the n → π* absorption band using NMR, UV-vis, and X-ray analysis. The data was used to establish and validate a computational approach that allows to compute realistic UV-vis spectra by combining TD-DFT excited-state calculations from 6000 thermally accessible structures generated through MD simulations while considering the high structural flexibility of ortho-substituted azobenzenes. We added 15 new visible light-operated photoswitches to the toolbox for the development of optical devices with relaxation rates across multiple orders of magnitude and identified several examples with stronger bathochromic shifts than the dfdc azobenzene lead structure. Our combined experimental and computational study forms the foundation for the advanced in silico design and synthesis of new highly red-shifted photoswitches. To showcase the potential of dfdc azobenzenes for the development of chemical tools, we synthesized dfdc-OptoBI-1 and demonstrated its biological activity as a red light-operated activator of TRPC6 channels in HEK293 cells.
偶氮苯是多功能光开关，可用于制造精密光学工具，包括光致药物。然而，针对特定性质的新型光开关进行靶向应用导向设计仍然具有挑战性。我们已经开发出了用于二邻氟二邻氯（dfdc）偶氮苯支架衍生物的合成方案，该衍生物在对位/邻位有化学变化，并利用核磁共振（NMR）、紫外可见光谱（UV-vis）和X射线分析，深入研究了其结构对光物理性质的影响，重点是n→π*吸收带。这些数据被用于建立和验证一种计算方法，该方法通过结合从分子动力学（MD）模拟生成的6000个热可及结构的含时密度泛函理论（TD-DFT）激发态计算来计算逼真的紫外可见光谱，同时考虑邻位取代偶氮苯的高结构灵活性。我们为光电器件开发工具箱增加了15种新型可见光操作光开关，其弛豫速率跨越多个数量级，并确定了几个比dfdc偶氮苯先导结构有更强红移的例子。我们结合实验和计算的研究为新型高红移光开关的先进计算机辅助设计和合成奠定了基础。为了展示dfdc偶氮苯在化学工具开发方面的潜力，我们合成了dfdc-OptoBI-1，并证明了它作为HEK293细胞中TRPC6通道的红光操作激活剂的生物活性。
