Belicchi Ferrari Marisa, Bisceglie Franco, Pelosi Giorgio, Tarasconi Pieralberto, Albertini Roberto, Dall'Aglio Pier Paolo, Pinelli Silvana, Bergamo Alberta, Sava Gianni
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica e Chimica Fisica, Parco Area delle Scienze 17 A, Università di Parma, I-43100 Parma, Italy.
J Inorg Biochem. 2004 Feb;98(2):301-12. doi: 10.1016/j.jinorgbio.2003.09.011.
A dimeric copper complex of the unsubstituted pyridoxal thiosemicarbazone (H(2)L), [Cu(HL)(OH(2))]Cl(2).2H(2)O, previously tested on Friend murine cell lines has been recently resynthesized to evaluate its behavior on different murine and human leukemic cell lines and has been compared, in vitro and in vivo, with its monomeric counterpart [Cu(H(2)L)(OH(2))Cl]Cl. On TS/A murine adenocarcinoma cell line in vitro, both compounds significantly inhibit cell proliferation at micromolar concentrations, although the dimeric compound is more active. Despite this cytotoxicity they lack in vivo activity on TLX5 lymphoma. The unsubstituted dimeric [Cu(HL)(OH(2))]Cl(2).2H(2)O induces apoptosis on CEM and U937 human cell lines, with IC(50) concentrations of 1.2 x 10(-5) and 6.7 x 10(-6) M, respectively, but it is inactive on K562. Moreover, it alters significantly the cell cycle of U937 and CEM lines and decreases the telomerase activity of U937. To verify if other dimeric copper complexes show relevant biological activity new complexes with N-substituted pyridoxal thiosemicarbazones have been synthesized and characterized using spectroscopic techniques. Three of them, namely Cu(Me(2)-HL)Cl.6H(2)O (Me(2)-H(2)L=pyridoxal N1,N1-dimethylthiosemicarbazone) (1), Cu(MeMe-HL)ClCl(2).4H(2)O (MeMe-HL=pyridoxal N1,N2-dimethylthiosemicarbazone) (2), Cu(Et-H(2)L)ClCl(2).2H(2)O (Et-H(2)L=pyridoxal N1-ethylthiosemicarbazone) (3), were also characterized by X-ray diffractometry. These complexes are dimeric and all three present a square pyramidal coordinative geometry with the ligand showing an SNO tridentate behavior. Their biological activities have been tested in vitro on U937, CEM and K562 cell lines to ascertain their effectiveness in comparison to the corresponding unsubstituted complex [Cu(HL)(OH(2))]Cl(2).2H(2)O. Compound 1 shows weak proliferation inhibition on all three cell lines, but it does not induce apoptosis and it does not inhibit telomerase activity, compound 2 is not effective at low concentration and is toxic at higher doses; compound 3 inhibits CEM cell growth better than complex 1 but it does not exert any other biological effect.
未取代的吡哆醛缩氨基硫脲（H₂L）的二聚铜配合物[Cu(HL)(OH₂)]Cl₂·2H₂O，此前已在Friend小鼠细胞系上进行过测试，最近又重新合成，以评估其在不同小鼠和人类白血病细胞系上的表现，并在体外和体内与它的单体对应物[Cu(H₂L)(OH₂)Cl]Cl进行了比较。在体外对TS/A小鼠腺癌细胞系进行测试时，两种化合物在微摩尔浓度下均能显著抑制细胞增殖，不过二聚体化合物的活性更强。尽管有这种细胞毒性，但它们对TLX5淋巴瘤缺乏体内活性。未取代的二聚体[Cu(HL)(OH₂)]Cl₂·2H₂O可诱导CEM和U937人类细胞系凋亡，IC₅₀浓度分别为1.2×10⁻⁵和6.7×10⁻⁶ M，但对K562细胞系无活性。此外，它能显著改变U937和CEM细胞系的细胞周期，并降低U937的端粒酶活性。为了验证其他二聚铜配合物是否具有相关生物活性，已合成了带有N-取代吡哆醛缩氨基硫脲的新配合物，并使用光谱技术对其进行了表征。其中三种，即[Cu(Me₂-HL)Cl]₂·6H₂O（Me₂-H₂L = 吡哆醛N1,N1-二甲基缩氨基硫脲）（1）、[Cu(MeMe-HL)Cl]₂Cl₂·4H₂O（MeMe-HL = 吡哆醛N1,N2-二甲基缩氨基硫脲）（2）、[Cu(Et-H₂L)Cl]₂Cl₂·2H₂O（Et-H₂L = 吡哆醛N1-乙基缩氨基硫脲）（3），还通过X射线衍射法进行了表征。这些配合物都是二聚体，且全部呈现出四方锥配位几何结构，配体表现出SNO三齿行为。已在体外对U937、CEM和K562细胞系测试了它们的生物活性，以确定与相应的未取代配合物[Cu(HL)(OH₂)]Cl₂·2H₂O相比，它们的有效性。化合物1对所有三种细胞系均显示出较弱的增殖抑制作用，但不诱导凋亡，也不抑制端粒酶活性；化合物2在低浓度时无效，在高剂量时有毒性；化合物3对CEM细胞生长的抑制作用优于配合物1，但不产生任何其他生物学效应。
