DNA binding of properties of trinuclear platinum complex

174

Journal of Inorganic Biochemistry

Abstracts

E35

DNA BINDING OF PROPERTIES OF TRINUCLEAR PLATINUM COMPLEX

Yun.Qu =, Nicholas Farrell", Jana Kasparkova b, Viktor Brabec b, Chemistry Department, Virginia Commonwealth University, Richmond, VA 23284-2006. t, h~stitute of Biophysics, Academy of Sciences, Brno, Czech Republic 61265

The novel multinuclear platinum compound BBR 3464 will enter Phase I clinical trials in late 1997. A systematic evaluation of bifianctional DNA-binding agents based on multinuclear platinum complexes identified BBR 3464 as an outstanding clinical candidate. BBR 3464 contains two transPtCI(NH3)2 traits linked by a NH2(CH2)6NH2-trans-Pt(NH3)2-NH2(CH2)6NH2 diamine chain (see structure below). The central Pt unit is only capable of H-bonding interactions with DNA. The initial studies show the overall charge (+4) and H-bonding capacity of BBR 3464 greatly enhances DNA affinity, which produce similar rb to CDDP at very low concentrations. The BBR 3464 is capable to achieve long-range crosslinking up to 6 base pairs apart, very efficient and irreversible conversion of ]3 to Z-form DNA, and significant unwinding. The structure of the DNA-triPt is different from CDDP. The adducts terminate DNA synthesis in vitro. These features are compared to the known DNA-binding profile of CDDP. The DNA binding properties may contribute to insensitivity of BBR 3464 to p53 status in CDDP-resistant ceils.

The work supported by American Cancer Society DHP-2E, Boehringer Mannheim Italia, and the Grant Agency of Czech Republic.

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3N\pt/NH2(CH2)6H2N~pt/NH3 Cl/

~NH3

H3N\pt/CI

H3N / '~NH2.(CH2)6H2N / ~NH3 Structureof BBR 3464

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