Pérez J M, Matesanz A I, Martín-Ambite A, Navarro P, Alonso C, Souza P
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Spain.
J Inorg Biochem. 1999 Jul 15;75(4):255-61. doi: 10.1016/s0162-0134(99)00096-3.
It is known that metallic complexes of methyl 2-pyridyl ketone thiosemicarbazone (HL1) and p-isopropyl benzaldehyde thiosemicarbazone (HL2) may have potential antitumor activity. We have prepared complexes of HL1 and HL2 with Zn(II) and Cd(II). The cytotoxic activity shown by these compounds against cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-DDP) indicates that coupling of HL1 and HL2 to Zn(II) and Cd(II) centers may result in metallic complexes with important biological properties since they display IC50 values in a microM range similar to that of the antitumor drug cis-DDP. Moreover, it is interesting to note that the Zn/HL2 complex exhibits specific cytotoxic activity against Pam-ras cells (cis-DDP resistant cells which over-express the H-ras oncogene) with an in vitro therapeutic index of 3.26 versus 0.78 for cis-DDP. Treatment of Pam-ras cells with the IC50 value of the Zn/HL2 compound induces a 'DNA ladder' (fragmentation of genomic DNA in nucleosome units) indicative of apoptosis in this ras-transformed cell line. In contrast, a 'DNA smear' (non-specific fragmentation of genomic DNA) is observed in Pam 212 normal cells treated with the IC50 of this compound. The analysis by circular dichroism (CD) spectroscopy of the interaction of the Zn/HL2 compound with calf thymus DNA (CT DNA) indicates that it produces stronger alterations on the double helix conformation than cis-DDP. So, these results suggest that Zn/HL2 may be considered a potential antitumor agent.
已知2-吡啶基甲基酮缩氨基硫脲（HL1）和对异丙基苯甲醛缩氨基硫脲（HL2）的金属配合物可能具有潜在的抗肿瘤活性。我们制备了HL1和HL2与锌（II）和镉（II）的配合物。这些化合物对顺二氨二氯铂（II）（顺铂）敏感和耐药的细胞系所表现出的细胞毒性活性表明，将HL1和HL2与锌（II）和镉（II）中心偶联可能会产生具有重要生物学特性的金属配合物，因为它们的半数抑制浓度（IC50）值在微摩尔范围内，与抗肿瘤药物顺铂相似。此外，值得注意的是，锌/HL2配合物对Pam-ras细胞（过表达H-ras癌基因的顺铂耐药细胞）表现出特异性细胞毒性活性，其体外治疗指数为3.26，而顺铂为0.78。用锌/HL2化合物的IC50值处理Pam-ras细胞会诱导出“DNA梯带”（基因组DNA在核小体单元中的片段化），这表明该ras转化细胞系发生了凋亡。相反，在用该化合物的IC50处理的Pam 212正常细胞中观察到“DNA拖尾”（基因组DNA的非特异性片段化）。通过圆二色性（CD）光谱分析锌/HL2化合物与小牛胸腺DNA（CT DNA）的相互作用表明，它对双螺旋构象的改变比顺铂更强。因此，这些结果表明锌/HL2可能被认为是一种潜在的抗肿瘤药物。
