Hu M, Brasseur N, Yildiz S Z, van Lier J E, Leznoff C C
Department of Chemistry, York University, Toronto, Ontario M3J 1P3, Canada.
J Med Chem. 1998 May 21;41(11):1789-802. doi: 10.1021/jm970336s.
A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.
一系列在3-、4-和4,5-位被苄基取代的邻苯二甲腈与邻苯二甲腈发生了不同的缩合反应，得到了一系列受保护的（单羟基和多羟基酞菁基）锌（II）衍生物，这些衍生物很容易被裂解，得到几种羟基酞菁（ZnPc）（酞菁酚类似物）。在EMT-6乳腺肿瘤细胞系上评估了它们作为癌症光动力疗法（PDT）敏化剂的功效。在体外，2-羟基ZnPc（32）活性最高，其次是2,3-和2,9-二羟基ZnPc（39和45），而2,9,16-三羟基ZnPc（33）活性最低。在体内，单羟基衍生物32和2,3-二羟基衍生物39在1 μmol kg-1时都能有效诱导肿瘤坏死，但即使在2 μmol/kg时，肿瘤完全消退情况也很差。相比之下，2,9-二羟基异构体45在2 μmol kg-1时，能使所有接受治疗的动物发生肿瘤坏死，75%完全消退。这些结果强调了酞菁大环上取代基位置对优化肿瘤反应的重要性，并证实了在相邻苯环上带有官能团的不对称酞菁的光动力疗法潜力。
