Vol. 58, Issue 6, 1525-1535, December 2000

Replacement of an NH₃ by an Iminoether in Transplatin Makes an Antitumor Drug from an Inactive Compound

Marc Leng, Daniel Locker, Marie-Josèphe Giraud-Panis, Annie Schwartz, Francesco P. Intini, Giovanni Natile, Claudio Pisano, Angelina Boccarelli, Domenico Giordano, and Mauro Coluccia

Centre de Biophysique Moléculaire, Centre National de la Recherche Scientifique, Orléans, France (M.L., D.L., M.G.P., A.S.); Department of Pharmaceutical Chemistry, Bari, Italy (F.P.I., G.N.); Department of Oncology, Sigma-tau, Pomezia, Italy (C.P.); and Department of Biomedical Sciences and Human Oncology, Bari, Italy (A.B., D.G., M.C.)

To investigate the modifications of antitumor activity and DNA binding mode of transplatin after replacement of one nonleaving group NH₃ by an iminoether group, trans-[PtCl₂{Z-HN=C(OMe)Me}(NH₃)] and trans-[PtCl₂{E-HN=C(OMe)Me}(NH₃)] complexes (differing in the Z or E configuration of iminoether, and abbreviated mixed Z and mixed E, respectively), have been synthesized. In a panel of human tumor cell lines, both mixed Z and mixed E show a cytotoxic potency higher than that of transplatin, the mean IC₅₀ values being 103, 37, and 215 µM, respectively. In vivo mixed Z is more active and less toxic than mixed E in murine P388 leukemia and retains its efficacy against SK-OV-3 human cancer cell xenograft in nude mice. In the reaction with naked DNA, mixed Z forms monofunctional adducts that do not evolve into intrastrand cross-links but close slowly into interstrand cross-links between complementary guanine and cytosine residues. The monofunctional mixed Z adducts are removed by thiourea and glutathione. The interstrand cross-links behave as hinge joints, increasing the flexibility of DNA double helix. The mixed Z, transplatin, and cisplatin interstrand cross-links, as well as mixed Z monofunctional adducts are not specifically recognized by HMG1 protein, which was confirmed to be able to specifically recognize cisplatin d(GpG) intrastrand cross-links. These data demonstrate that the DNA interaction properties of the antitumor-active mixed Z are very similar to those of transplatin, thus suggesting that clinical inactivity of transplatin could not depend upon its peculiar DNA binding mode.