Fisher Dianne M, Bednarski Patrick J, Grünert Renate, Turner Peter, Fenton Ronald R, Aldrich-Wright Janice R
Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, NSW 2006, Australia.
ChemMedChem. 2007 Apr;2(4):488-95. doi: 10.1002/cmdc.200600211.
Four platinum(II) metallointercalating complexes of 1,10-phenanthroline (phen) with the chiral ancillary ligands trans-R,R- and trans-S,S-1,2-diaminocyclohexane (R,R- and S,S-dach, respectively), and N,N'-dimethyl-R,R- and N,N'-dimethyl-S,S-1,2-diaminocyclohexane (Me(2)-R,R-dach and Me(2)-S,S-dach, respectively) have been synthesised and characterised. The crystal structure of Pt(Me(2)-S,S-dach)(phen)(2)1.5 H(2)O (C(20)H(26)Cl(2)N(4)O(9.5)Pt) has been determined; orthorhombic, space group P2(1)2(1)2(1)(No. 19), a=23.194(8), b=25.131(9), c=8.522(3) A. In vitro cytotoxic assays (IC(50)) in the human bladder cancer cell line 5637 and in the murine leukemia L1210 cell line revealed that Pt(S,S-dach)(phen)(2) (0.091 and 0.13 microM, respectively) and Pt(R,R-dach)(phen)(2) (0.54 and 1.50 microM, respectively) were more cytotoxic than cisplatin (0.31 and 0.50 microM, respectively) and considerably more cytotoxic than their methylated counterparts, Pt(Me(2)-R,R-dach)(phen)(2) and Pt(Me(2)-S,S-dach)(phen)(2) (both>23 microM). Chiral discrimination for Pt(S,S-dach)(phen)(2) over its R,R-enantiomer was observed in all 13 cancer cell lines investigated. Moreover, Pt(S,S-dach)(phen)(2) was more active than cisplatin in all cell lines tested and shows only partial cross-resistance to cisplatin in two cisplatin resistant cell lines.
合成并表征了四种1,10 - 菲咯啉（phen）与手性辅助配体反式 - R,R - 和反式 - S,S - 1,2 - 二氨基环己烷（分别为R,R - 和S,S - dach）以及N,N'-二甲基 - R,R - 和N,N'-二甲基 - S,S - 1,2 - 二氨基环己烷（分别为Me(2)-R,R - dach和Me(2)-S,S - dach）形成的铂（II）金属插入配合物。已测定Pt(Me(2)-S,S - dach)(phen)(2)·1.5H(2)O（C(20)H(26)Cl(2)N(4)O(9.5)Pt）的晶体结构；正交晶系，空间群P2(1)2(1)2(1)（编号19），a = 23.194(8)，b = 25.131(9)，c = 8.522(3) Å。在人膀胱癌细胞系5637和小鼠白血病L1210细胞系中的体外细胞毒性测定（IC(50)）表明，Pt(S,S - dach)(phen)(2)（分别为0.091和0.13 μM）和Pt(R,R - dach)(phen)(2)（分别为0.54和1.50 μM）比顺铂（分别为0.31和0.50 μM）细胞毒性更强，且比其甲基化对应物Pt(Me(2)-R,R - dach)(phen)(2)和Pt(Me(2)-S,S - dach)(phen)(2)（均>23 μM）细胞毒性大得多。在所有研究的13种癌细胞系中均观察到Pt(S,S - dach)(phen)(2)对其R,R - 对映体的手性识别。此外，Pt(S,S - dach)(phen)(2)在所有测试细胞系中比顺铂更具活性，并且在两种顺铂耐药细胞系中仅表现出对顺铂的部分交叉耐药性。
