Costa Bruna D P, Simões João C S, Lopes Susana M M, Laranjo Mafalda, Rodrigues Ana Clara B, Gonçalves Ana Cristina, Seixas de Melo J Sérgio, Botelho M Filomena, Pineiro Marta, Pinho E Melo Teresa M V D
University of Coimbra, Coimbra Chemistry Centre-Institute of Molecular Sciences (CQC-IMS) and Department of Chemistry, 3004-535 Coimbra, Portugal.
University of Coimbra, Faculty of Medicine, Biophysics Institute, 3000-370 Coimbra, Portugal.
J Med Chem. 2024 Dec 26;67(24):21934-21951. doi: 10.1021/acs.jmedchem.4c01824. Epub 2024 Oct 4.
A synthetic route to -AB-corroles combining the macrocyclic core with a hydrazone moiety, based on the reactivity of azoalkenes toward dipyrromethanes, has been established with the aim of developing a new class of photosensitizers for photodynamic therapy of lung cancer. The study of the photophysical properties of the novel macrocycles allowed the identification of photosensitizers with absorption within the phototherapeutic window and high singlet oxygen quantum yield. Relevant structure-photodynamic activity correlations were established by studying the new corroles-based photodynamic therapy (PDT) in human lung cancer cell lines (A549 and H1299). The methyl-hydrazone corroles were more active than phenyl-hydrazone corroles, with the -Boc and -Ts groups being key structural features to ensure high activity. The lead photosensitizers, with IC values below 100 nM and no cytotoxicity per se, were significantly more active than 5,10,15-triphenylcorrole, showing that the presence of the hydrazone functional group has a strong influence on PDT activity.
基于偶氮烯烃对二吡咯甲烷的反应性，建立了一种将大环核心与腙部分相结合的合成路线，用于合成-AB-卟吩，目的是开发一类用于肺癌光动力治疗的新型光敏剂。对新型大环化合物光物理性质的研究使得能够鉴定出在光治疗窗口内具有吸收且单线态氧量子产率高的光敏剂。通过在人肺癌细胞系（A549和H1299）中研究基于新型卟吩的光动力疗法（PDT），建立了相关的结构-光动力活性相关性。甲基腙卟吩比苯基腙卟吩更具活性，-Boc和-Ts基团是确保高活性的关键结构特征。先导光敏剂的IC值低于100 nM且本身无细胞毒性，其活性明显高于5,10,15-三苯基卟吩，表明腙官能团的存在对PDT活性有很大影响。
