Preparation, DNA Binding, and in Vitro Cytotoxicity of a Pair of Enantiomeric Platinum(II) Complexes, [(R)- and (S)-3-Aminohexahydroazepine]dichloro- platinum(II). Crystal Structu
详细信息 查看全文
- 作者：Ronald R. Fenton ; Warren J. Easdale ; H. Meng Er ; Shaun M. O'Mara ; Mark J. McKeage ; Pamela J. Russell ; and Trevor W. Hambley
- 刊名：Journal of Medicinal Chemistry
- 出版年：1997
- 出版时间：March 28, 1997
- 年：1997
- 卷：40
- 期：7
- 页码：1090 - 1098
- 全文大小：258K
- 年卷期：v.40,no.7(March 28, 1997)
- ISSN：1520-4804
文摘
A pair of enantiomeric Pt(II) complexes,[Pt(R-ahaz)Cl2] and[Pt(S-ahaz)Cl2] (ahaz =3-aminohexahydroazepine), has been investigated for their ability to bindenantioselectively to DNA.Improved synthetic procedures were developed for preparing boththe ligands and the Ptcomplexes. The structure of the complex of the Senantiomer was determined by X-raycrystallographic methods. Crystals of[Pt(S-ahaz)Cl2] are orthorhombic,space groupP212121,with a = 6.917(1) Å, b = 11.167(1)Å, c = 12.373(2) Å, Z = 4, and thestructure was refined toR = 0.023 (1505F). Molecular modelingtechniques were used to investigate the role of stericinteractions between the ligand and DNA in influencing the bifunctionalbinding of the twoenantiomers, and it was found that the S enantiomer shouldbind more readily. The bindingof the S enantiomer, to calf thymus DNA, was indeed found tobe slightly greater than that forthe R enantiomer though slightly less than that forcis-DDP. Assays of the proportion ofmonofunctional adducts showed that a substantially greater proportionof monofunctionaladducts remained for the R enantiomer and cisplatin than forthe S enantiomer. Each of theenantiomers was subjected to in vitro cytotoxicity assaysusing cultures of human bladder (BL13/0), lung and resistant lung (PC9 and PC9cisR), and prostate (DU145)cancer cells. The Renantiomer was found to be slightly more cytotoxic in the bladder cellline and may be lesscytotoxic in the lung cell line but there were no significantdifferences in the resistant cell linenor in the prostate cell line. The two enantiomers were taken upequally by the bladder cancercells.