Substitution-inert trinuclear platinum complexes efficiently condense/aggregate nucleic acids and inhibit enzymatic activity

摘要

The trinuclear platinum complexes ([{Pt(NH3)3}2-μ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}]⁶⁺, TriplatinNC‐A; [{trans-Pt(NH3)2(NH2(CH2)6NH3⁺)}₂-μ-{trans-Pt(NH₃)₂(NH₂(CH₂)₆NH₂)₂}]⁸⁺, TriplatinNC) belong to a class of biologically active agents that bind to DNA via nonbonding noncovalent (hydrogen bonding, electrostatic) interactions. Charge delocalization (6+ to 8+) in these linear trinuclear platinum complexes results in a high cellular uptake and promising cytotoxic activity in several carcinoma cell lines. We show in the present work with the aid of the methods of biophysical chemistry that in particular TriplatinNC condenses DNA with unprecedented potency which is much higher than that of conventional DNA condensing agents. In addition, in contrast to other DNA condensing agents, both platinum complexes induce aggregation of small transfer RNA molecules. We also demonstrate for the first time that TriplatinNC-A and TriplatinNC in particular completely inhibit DNA transcriptional activity at markedly lower concentration than naturally occurring spermine. Notably, the topoisomerase I-mediated relaxation of supercoiled DNA was inhibited by TriplatinNC-A and TriplatinNC at ~60-fold and ~250-fold lower concentration than that of spermine, respectively. We suggest that the general mechanisms of biological activity of TriplatinNC-A and TriplatinNC may be associated with their unique ability to condense/aggregate nucleic acids with consequent inhibitory effect on crucial enzymatic activities.