University of Coimbra, Coimbra Chemistry Center - Institute of Molecular Sciences (CQC-IMS) and Department of Chemistry, 3004-535 Coimbra, Portugal.
University of Coimbra, Coimbra Chemistry Center - Institute of Molecular Sciences (CQC-IMS) and Department of Chemistry, 3004-535 Coimbra, Portugal; BSIM Therapeutics, Instituto Pedro Nunes, 3030-199 Coimbra, Portugal.
Bioorg Med Chem. 2023 Oct 1;93:117443. doi: 10.1016/j.bmc.2023.117443. Epub 2023 Aug 12.
Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.
光动力疗法（PDT）是一种成熟的抗癌治疗方法，它结合使用光敏剂（PS）和特定波长的光源，以产生对肿瘤细胞有毒的活性氧（ROS）。Foscan®（mTHPC）是一种临床批准的用于治疗晚期头颈部、前列腺和胰腺癌的卟啉类药物，但它的特点是光化学不稳定，并伴有长时间的皮肤光敏性。在此，我们通过探索间四（3-羟基苯基）卟啉衍生物与二氮杂富烯甲叉的[8π+2π]环加成反应，合成了具有 mTHPC 的中四（3-羟基苯基）大环核心的新型 4,5,6,7-四氢吡唑并[1,5-a]吡啶并卟啉类化合物。这些卟啉类化合物具有与 Foscan®相似的光化学性质，但光稳定性要强得多。在这些新型化合物中，两个在 4,5,6,7-四氢吡唑并[1,5-a]吡啶并稠合系统中带有羟甲基和叠氮化物的化合物，是具有 100 nM 范围内对三阴性乳腺癌细胞活性的有前途的光动力治疗剂，并且在叠氮甲基卟啉类化合物的情况下，与 Foscan®相比，具有更安全的光治疗指数。
