X-Ray structure of cytotoxic trans-[PtCl(2)(dimethylamine)(isopropylamine)]: interstrand cross-link efficiency, DNA sequence specificity, and inhibition of the B-Z transition

J Med Chem. 2000 Jun 15;43(12):2411-8. doi: 10.1021/jm000925p.

Abstract

We report here the X-ray structure of cytotoxic trans-¿PtCl(2)(dimethylamine)(isopropylamine). This trans-platinum compound crystallizes in the monoclinic system, with Z = 8, in the spatial group C2/c with unit cell parameters a = 19.862(17) A, b = 6. 581(3) A, c = 18.563(3) A, alpha = 90 degrees, beta = 119.16(3) degrees, gamma = 90 degrees, V = 2119(2) A(3), rho = 2.321 Mg/m(3), R = 0.0505, and R(w) = 0.1166 on the basis of 2339 independent reflections. To our knowledge this is the first report of the crystal structure of a biologically active trans-platinum compound containing different aliphatic amines. The DNA binding mode of trans-¿PtCl(2)(dimethylamine)(isopropylamine) may be a consequence of the spatial disposition of the dimethylamine and isopropylamine ligands around the trans-Pt(II) center. We have found that trans-¿PtCl(2)(dimethylamine)(isopropylamine) readily forms DNA interstrand cross-links. In addition, the compound shows binding affinity toward alternating purine-pyrimidine sequences and inhibits the B-Z transition. These particular DNA binding properties might be related to the capacity of trans-¿PtCl(2)(dimethylamine)(isopropylamine) for inducing some selective killing in a H-ras overexpresssing cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Circular Dichroism
  • Cross-Linking Reagents / chemistry*
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA, Superhelical / chemistry
  • Kinetics
  • Organoplatinum Compounds / chemistry*
  • Polydeoxyribonucleotides / chemistry
  • Sodium Chloride / chemistry

Substances

  • Antineoplastic Agents
  • Cross-Linking Reagents
  • DNA, Superhelical
  • Organoplatinum Compounds
  • Polydeoxyribonucleotides
  • dichloro(isopropylamine)(dimethylamine)platinum(II)
  • poly(dC-dG)
  • Sodium Chloride
  • DNA