Synthesis, Crystal Structure, Antitumor Activity, and DNA-Binding Properties of the New Active Platinum Compound (Bis(N-methylimidazol-2-yl)carbinol)dichloroplatinum(II), Lacking a NH Moiety, a
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- 作者：Marieke J. Bloemink ; Holger Engelking ; Stefan Karentzopoulos ; Bernt Krebs ; and Jan Reedijk
- 刊名：Inorganic Chemistry
- 出版年：1996
- 出版时间：January 31, 1996
- 年：1996
- 卷：35
- 期：3
- 页码：619 - 627
- 全文大小：368K
- 年卷期：v.35,no.3(January 31, 1996)
- ISSN：1520-510X
文摘
To obtain insight into the structure-activityrelationships of new antitumor active platinum compounds theX-raystructure of the antitumor active Pt compound[Pt(bmic)Cl2] (bmic =bis-(N-methylimidazol-2-yl)carbinol)(1)and its interaction with short DNA fragments has been investigatedusing NMR spectroscopy. For comparisonalso the structurally related compound[Pt(bmi)Cl2] (bmi =N1,N1'-dimethyl-2,2'-biimidazole)(2), which is notantitumor active, has been studied. The structure of the compound[Pt(bmic)Cl2] (1) was characterizedby single-crystal X-ray structure determination. Compound 1crystallizes in the monoclinic space groupP21/n, with a=10.055(3) Å, b = 11.802(3) Å, c =10.620(3) Å, 
= 103.78(2)
, V =1224.0(6) Å3 and Z = 4.Convergencewas reached at wR2 = 0.1148 (all data) and R1 = 0.0476(I > 2 (I)) for 2433 independent reflections and156adjustable parameters. The platinum atom is coordinated by twonitrogen and two chlorine atoms, resulting ina square planar PtN2Cl2 coordinationsphere. The two best least-squares planes through the twoimidazole ringsof the bmic ligand show a dihedral angle of 30.6. The invitro and in vivo antitumor activity of 1 issignificantwhereas for compound 2 no antitumor activity could bedetected. In P388 mice leukemia an increase oflifespanof 56% was found for complex 1. The antitumor activePt compound [Pt(bmic)Cl2] binds to G bases in asimilarfashion as cisplatin with a clear preference for N7. In reactionwith d(GpG) two stereoisomers are formed, dueto the unsymmetric bmic complex and the chiral d(GpG) molecule.Stereoisomer A, i.e. the isomer with theOHgroup of the bmic and the O6 of the G bases oriented on the same sideof the Pt-N4 plane, is preferentiallyformed. Modeling studies suggest that this preference is due tothe presence of H bonds from the OH of thebmic moiety toward the O6 of the G bases. The presence of manyconformers, present in solution, could also bedue to these H bonds. For the inactive complex[Pt(bmi)Cl2] only oneGG-N7,N7 chelate is observed.Differencesin reactivity toward G bases were also detected for the two platinumcomplexes. The inactive bmi complexproves to be the most reactive one, whereas the antitumor active bmiccompound is less reactive. Thus bothstructural and kinetic properties may explain the different biologicalproperties of these new platinum compounds.
= 103.78(2), V =1224.0(6) Å3 and Z = 4.Convergencewas reached at wR2 = 0.1148 (all data) and R1 = 0.0476(I > 2 (I)) for 2433 independent reflections and156adjustable parameters. The platinum atom is coordinated by twonitrogen and two chlorine atoms, resulting ina square planar PtN2Cl2 coordinationsphere. The two best least-squares planes through the twoimidazole ringsof the bmic ligand show a dihedral angle of 30.6. The invitro and in vivo antitumor activity of 1 issignificantwhereas for compound 2 no antitumor activity could bedetected. In P388 mice leukemia an increase oflifespanof 56% was found for complex 1. The antitumor activePt compound [Pt(bmic)Cl2] binds to G bases in asimilarfashion as cisplatin with a clear preference for N7. In reactionwith d(GpG) two stereoisomers are formed, dueto the unsymmetric bmic complex and the chiral d(GpG) molecule.Stereoisomer A, i.e. the isomer with theOHgroup of the bmic and the O6 of the G bases oriented on the same sideof the Pt-N4 plane, is preferentiallyformed. Modeling studies suggest that this preference is due tothe presence of H bonds from the OH of thebmic moiety toward the O6 of the G bases. The presence of manyconformers, present in solution, could also bedue to these H bonds. For the inactive complex[Pt(bmi)Cl2] only oneGG-N7,N7 chelate is observed.Differencesin reactivity toward G bases were also detected for the two platinumcomplexes. The inactive bmi complexproves to be the most reactive one, whereas the antitumor active bmiccompound is less reactive. Thus bothstructural and kinetic properties may explain the different biologicalproperties of these new platinum compounds.