Charge delocalization (6+ to 8+) in "noncovalent" linear trinuclear platinum complexes produces compounds with cytotoxicity in some cases equivalent to cisplatin. The cellular uptake of a novel 8+ compound is greater than that of neutral cisplatin as well as other multinuclear Pt compounds.

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ABSTRACT[{trans-PtCl(NH 3 ) 2 } 2 -(trans-Pt(NH 3 ) 2 (H 2 N(CH 2 ) 6 NH 2 ) 2 )] 4ϩ (BBR 3464) is a 4ϩ cationic trinuclear platinum drug that has undergone phase II clinical trials in the treatment of ovarian and lung cancers. The chemical structure of BBR 3464 is distinct from that of clinically used agents such as cisplatin and oxaliplatin. As a consequence, the modes of DNA binding and the structures of BBR 3464 DNA adducts are also structurally distinct from those formed by cisplatin and oxaliplatin. Previous chemical and spectroscopic measurements on BBR 3464 had elucidated a significant noncovalent contribution to DNA binding. To examine this effect further, the biological activity of two BBR 3464 analogs that bind DNA only through noncovalent interactions was investigated in this study, and their cellular effects were compared with those caused by the "parent" drug. The compounds were [{trans-PtL(NH 3 ) 2 } 2 -(transPt(NH 3 ) 2 (H 2 N(CH 2 ) 6 NH 2 ) 2 )] nϩ , with L ϭ NH 3 , n ϭ 6 for compound I, and L ϭ H 2 N(CH 2 ) 6 NH 3 , n ϭ 8 for compound II. All compounds induce caspase-dependent apoptosis in both primary mast cells and transformed mastocytomas, although with a smaller IC 50 value in the transformed cells. In cells deficient in either the tumor suppressor proteins p53 or Bax, apoptosis was least affected in the case of II, but in all cases the effect of p53 deficiency was greater than that of Bax. Surprisingly, cellular uptake was actually enhanced for the more highly charged compounds, resulting in significant (micromolar) cyotoxicity for II. Cellular accumulation was enhanced in mastocytomas over primary mast cells, suggesting a mechanism for enhancement of tumor cell selectivity.

The trinuclear compound [{Pt(NH3)3}2mu-{trans-Pt(NH3)2(H2N(CH2)6NH2)}2(6+) (0,0,0/t,t,t) binds to DNA only through noncovalent hydrogen bonding and electrostatic interactions. The presence of this 6+ cation allows discrimination of binding modes for common DNA ligands: binding of minor-groove agents such as Hoechst 33258 is cooperative, and dye-DNA interaction is enhanced whereas intercalation as exemplified by ethidium bromide is competitively inhibited.

Polynuclear platinum compounds (PPCs) represent a discrete class of antitumor agents that bear structural resemblance to polyamines. This chapter reviews developments on the chemistry and biology of polynuclear platinum drugs and especially the recognition that “non-covalent” agents based on this motif represent a further challenge to the structure-activity paradigms for platinum antitumor agents. Pt-DNA bond formation is not a strict requirement for DNA affinity leading to manifestation of promising cytotoxicity and antitumor activity. Non-covalent PPCs bind to DNA in a non-covalent manner through a novel binding motif, the phosphate clamp, analogous to the arginine fork. This binding mode is discrete from “classical” intercalation and minor groove binding. In solution, analysis of 1-D and 2-D 1HNMR data places the compounds in the minor groove of the DNA, spanning several base pairs. A melphalan protection assay indicated that the complex was at least as effective in blocking melphalan access to the minor groove as distamycin. Further biological consequences of the structure are remarkably enhanced cellular accumulation, further distinguishing the non-covalent group as a unique class of agents.