The biological activities of 5,15-diaryl-10,20-dihalogeno porphyrins for photodynamic therapy.

PURPOSE: Esophageal cancer is the most common gastrointestinal tumor and is difficult to be eradicated with conventional treatment. Porphyrin-based photosensitizers (PSs) mediated photodynamic therapy (PDT) could kill tumor cells with less damage to normal cells. As the most widely used porphyrin-based photosensitizer in clinics, Photofrin II has excellent anti-tumor effect. However, it has some disadvantages such as weak absorption at near infrared region, the complexity of components and prolonged skin photosensitivity. Here series novel 5,15-diaryl-10,20-dihalogeno porphyrin derivatives were afforded and evaluated to develop more effective and safer photosensitizers for tumor therapy. METHODS: The photophysical properties and singlet oxygen generation rates of 5,15-diaryl-10,20-dihalogeno porphyrins (I1-6, II1-4) were tested. The cytotoxicity of I1-6 and II1-4 were measured by MTT assay. The pathway of cell death was studied by flow cytometry. In vivo photodynamic efficacy of I3 and II2-4 in Eca-109 tumor-bearing BABL/c nude mice were measured and histopathological analysis were examined. RESULTS: 5,15-Diaryl-10,20-dihalogeno porphyrins I1-6 and II1-4 were synthesized. The longest absorption wavelength of these halogenated porphyrins (λmax = 660 nm) displayed a red shift around 30 nm compared to the unhalogenated porphyrins PS1 (λmax = 630 nm). The singlet oxygen generation rates of I1-6 and II1-4 were significantly higher than PS1 and HMME. All PSs mediated PDT showed obvious cytotoxic effect against Eca-109 cells compared to HMME in vitro and in vivo. Among these PSs, II4 exhibited appropriate absorption in the phototherapeutic window, higher 1O2 generation rate (k = 0.0061 s-1), the strongest phototoxicity (IC50 = 0.4 µM), lower dark toxicity, high generation of intracellular ROS in Eca-109 cells and excellent photodynamic anti-tumor efficacy in vivo. Besides, cell necrosis was induced by compound II4 mediated PDT. CONCLUSION: All new compounds have obvious photodynamic anti-esophageal cancer effects. Among them, the photosensitizer II4 showed excellent efficacy in vitro and in vivo, which has the potential to become a photodynamic anti-tumor drug.

Clavariopsins C-I, Antifungal Cyclic Depsipeptides from the Aquatic Hyphomycete Clavariopsis aquatica.

Seven new cyclic depsipeptides, clavariopsins C-I (3-9), together with two known congeners, clavariopsins A and B (1 and 2), were isolated from the aquatic hyphomycete Clavariopsis aquatica. Their planar structures, which consist of nine amino acids and one α-hydroxy acid, were elucidated by NMR spectroscopy and HRESIMS. The absolute configurations were established by the advanced Marfey's method and chiral-phase HPLC analysis. Their antifungal and cytotoxic activities were evaluated against six plant pathogenic fungi (Botrytis cinerea, Magnaporthe oryzae, Colletotrichum orbiculare, Fusarium oxysporum, Alternaria alternata, and Aspergillus niger) and a cancer cell line (HeLa-S3), respectively. The majority of the compounds exhibited potent antifungal activity against the fungi tested (minimum inhibition dose = 0.01-10 µg/disk) and induced hyphal swelling in A. niger (minimum effective dose = 0.3-3 µg/disk), whereas the compounds exhibited no cytotoxicity toward the cancer cell line. The results suggest that the clavariopsins could be a promising class of antifungal agents.