Bordin F, Carlassare F, Conconi M T, Capozzi A, Majone F, Guiotto A, Baccichetti F
Department of Pharmaceutical Sciences, Padua University, Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del CNR, Italy.
Photochem Photobiol. 1992 Feb;55(2):221-9. doi: 10.1111/j.1751-1097.1992.tb04231.x.
The biological activity of some benzopsoralen derivatives, prepared with the aim of obtaining new drugs for photochemotherapy, has been studied. The more interesting compounds are 4-hydroxymethyl-4',5'-benzopsoralen and 4-hydroxymethyl-4',5'-tetrahydro-benzopsoralen, which were found to be active in the dark also: DNA and RNA synthesis were both inhibited in Ehrlich cells, even if in a partially reversible fashion, while protein synthesis remained unaffected. In Chinese hamster ovary cells cultured in vitro, the clonal growth was strongly inhibited by incubation in the dark with both drugs, while a number of chromosomal aberrations was observed in the fraction of growing cells. Using alkaline elution, DNA strand breaks were detected. In addition, in the presence of aphidicolin, a specific inhibitor of DNA polymerase, the clonal growing capacity was completely restored; in contrast, the number of DNA strand breaks remained unchanged. All these results suggest that DNA topoisomerases are probably the target of these two benzopsoralens. These compounds are also good sensitizers; by UV-A irradiation they have a good capacity to produce singlet oxygen, but they appeared to be unable to induce erythemas on guinea-pig skin. Under UV-A light, they induced a strong inhibition of DNA synthesis in Ehrlich cells. Thus, benzopsoralens appear to be capable of inducing strong antiproliferative effects by two different mechanisms, by UV-A irradiation and in the dark.
为了获得用于光化学疗法的新药而制备的一些苯并补骨脂素衍生物的生物活性已得到研究。更有趣的化合物是4-羟甲基-4',5'-苯并补骨脂素和4-羟甲基-4',5'-四氢苯并补骨脂素，它们在黑暗中也具有活性：在艾氏腹水癌细胞中，DNA和RNA的合成均受到抑制，即使这种抑制是部分可逆的，而蛋白质合成则不受影响。在体外培养的中国仓鼠卵巢细胞中，用这两种药物在黑暗中孵育会强烈抑制克隆生长，同时在正在生长的细胞部分中观察到一些染色体畸变。使用碱性洗脱法检测到了DNA链断裂。此外，在存在DNA聚合酶特异性抑制剂阿非科林的情况下，克隆生长能力完全恢复；相反，DNA链断裂的数量保持不变。所有这些结果表明，DNA拓扑异构酶可能是这两种苯并补骨脂素的作用靶点。这些化合物也是良好的敏化剂；通过紫外线A照射，它们具有产生单线态氧的良好能力，但它们似乎无法在豚鼠皮肤上诱发红斑。在紫外线A光下，它们在艾氏腹水癌细胞中诱导了DNA合成的强烈抑制。因此，苯并补骨脂素似乎能够通过两种不同机制诱导强烈的抗增殖作用，即通过紫外线A照射和在黑暗中发挥作用。
