Richert C, Wessels J M, Müller M, Kisters M, Benninghaus T, Goetz A E
Institute for Organic Chemistry, University Cologne, Köln, Germany.
J Med Chem. 1994 Aug 19;37(17):2797-807. doi: 10.1021/jm00043a019.
Porphycene photosensitizers bearing two or four methoxyethyl side chains were synthesized in nine steps from commercially available starting materials. Ether cleavage led to (hydroxyethyl)- and (bromoethyl)porphycenes that were converted to vinyl and benzo derivatives. Five of the side chain-functionalized porphycenes were biologically studied in comparison with two tetra-n-propylporphycenes. Porphycenes were incorporated in small unilamellar liposomes and incubated with cultivated SSK2 murine fibrosarcoma cells. Cellular uptake and phototoxicity 24 h after 5 J/cm2 laser light treatment were determined. The porphycenes tested were between 17 and 220 times more photodynamically active than the currently clinically used sensitizer Photofrin, although extinction coefficients of the porphycenes' irradiated bands are only approximately 10-fold higher. The LD50 concentration for SSK2 cells in the incubation medium was as low as (8.5 +/- 2.8) x 10(-9) M for tetrakis(methoxyethyl)porphycene. Two methoxy or hydroxy groups enhanced cellular uptake, three or four methoxy groups both enhanced and accelerated cellular uptake of tetraalkylporphycenes. Half-life times of the uptake processes varied between (0.14 +/- 0.04) and (14 +/- 4) h and cellular saturation levels between (1.2 +/- 0.2) and (26 +/- 3) pmol/10(5) cells. When individual uptake rates were accounted for, all porphycenes had a similar "cellular" phototoxicity, pointing toward a common mechanism of action. Evidence is presented for the assumption that cell membranes are the primary targets of the tested porphycenes and that membrane solubility may play a critical role in their photodynamic efficiency. The results show that nonionic polar side chain functionalities can strongly enhance cellular uptake and antitumor activity of lipophilic porphyrinoids and thus that the known lipophilicity/activity relationship can be reversed for very hydrophobic sensitizers.
从市售起始原料经九步合成了带有两个或四个甲氧基乙基侧链的卟吩光敏剂。醚键裂解生成（羟乙基）-和（溴乙基）卟吩，它们可转化为乙烯基和苯并衍生物。将五个侧链功能化的卟吩与两种四正丙基卟吩进行了生物学比较研究。将卟吩掺入小单层脂质体中，并与培养的SSK2小鼠纤维肉瘤细胞一起孵育。测定了5 J/cm2激光照射处理24小时后的细胞摄取和光毒性。所测试的卟吩的光动力活性比目前临床上使用的敏化剂Photofrin高17至220倍，尽管卟吩照射带的消光系数仅高约10倍。对于四（甲氧基乙基）卟吩，孵育培养基中SSK2细胞的LD50浓度低至(8.5±2.8)×10(-9) M。两个甲氧基或羟基增强细胞摄取，三个或四个甲氧基既增强又加速四烷基卟吩的细胞摄取。摄取过程的半衰期在(0.14±0.04)至(14±4)小时之间变化，细胞饱和水平在(1.2±0.2)至(26±3) pmol/10(5)细胞之间。当考虑个体摄取率时，所有卟吩具有相似的“细胞”光毒性，表明存在共同的作用机制。有证据支持这样的假设，即细胞膜是所测试卟吩的主要靶标，并且膜溶解性可能在其光动力效率中起关键作用。结果表明，非离子极性侧链官能团可强烈增强亲脂性卟啉类化合物的细胞摄取和抗肿瘤活性，因此对于非常疏水的敏化剂，已知的亲脂性/活性关系可以逆转。
