Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.
Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France; Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Bioorg Med Chem. 2019 Jun 15;27(12):2666-2675. doi: 10.1016/j.bmc.2019.05.011. Epub 2019 May 10.
The use of Photodynamic Therapy (PDT) for the treatment of several kinds of cancer as well as bacterial, fungal or viral infections has received increasing attention during the last decade. However, the currently clinically approved photosensitizers (PSs) have several drawbacks, including photobleaching, slow clearance from the organism and poor water solubility. To overcome these shortcomings, many efforts have been made in the development of new types of PSs, such as Ru(II) polypyridyl complexes. Nevertheless, most studied Ru(II) polypyridyl complexes have a low absorbance in the spectral therapeutic window. In this work, we show that, by carefully selecting substituents on the polypyridyl complex, it is possible to prepare a complex absorbing at a much higher wavelength. Specifically, we report on the synthesis as well as in-depth experimental and theoretical characterisation of a Ru(II) polypyridyl complex (complex 3) combining a shift in absorbance towards the spectral therapeutic window with a high O production. To overcome the absence or poor selectivity of most approved PSs into targeted cells/bacteria, they can be linked to targeting moieties. In this line, compound 3 was designed with reactive aldehyde groups, which can be used as a highly versatile synthetic precursor for further conjugation. As a proof of concept, 3 was reacted with benzylamine and the stability of the resulting conjugate 4 was investigated in DMSO, PBS and cell media. 4 showed an impressive ability to act as a PDT PS with no measurable dark cytotoxicity and photocytotoxicity in the low micromolar range against cancerous HeLa cells from 450 nm up to 540 nm.
在过去十年中，光动力疗法（PDT）在治疗多种癌症以及细菌、真菌或病毒感染方面受到了越来越多的关注。然而，目前临床批准的光敏剂（PSs）存在一些缺点，包括光漂白、从生物体中缓慢清除和低水溶性。为了克服这些缺点，人们在开发新型 PSs 方面做出了许多努力，例如 Ru(II) 多吡啶配合物。然而，大多数研究过的 Ru(II) 多吡啶配合物在光谱治疗窗口中的吸收较低。在这项工作中，我们表明，通过仔细选择多吡啶配合物上的取代基，可以制备在更高波长处吸收的配合物。具体来说，我们报告了 Ru(II) 多吡啶配合物（配合物 3）的合成以及深入的实验和理论表征，该配合物将吸收光谱移至光谱治疗窗口，并具有较高的 O 产生。为了克服大多数批准的 PSs 进入靶向细胞/细菌时的缺乏或选择性差，可以将其与靶向部分连接。在这方面，设计了具有反应性醛基的化合物 3，其可用作进一步缀合的高度通用的合成前体。作为概念验证，3 与苄胺反应，并研究了所得缀合物 4 在 DMSO、PBS 和细胞培养基中的稳定性。4 表现出令人印象深刻的能力，可作为 PDT PS，在低微摩尔范围内对来自 450nm 至 540nm 的癌细胞没有可测量的暗细胞毒性和光细胞毒性。
