Dinuclear Platinum Complexes Containing Planar Aromatic Ligands to Enhance Stacking Interactions with Proteins

作者：Ma Erin S F^*; Daniel A Gerard; Farrell Nicholas P

来源：ChemMedChem, 2014, 9(6): 1155-1160.

DOI：10.1002/cmdc.201402052

• heterocycles
• pi-pi stacking
• platinum
• protein recognition
• tryptophan

In an approach to design drugs with higher affinity for - stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2(L)}2--{trans-1,4-dach}](NO3)4 ((A)2=(NH3)2 or ethylenediamine (en), L=quinoline (quin) or benzothiazole (bztz), dach=trans-1,4-diaminocyclohexane) were synthesized. The quinoline complex, [{cis-Pt(en)(quin)}2--(dach)](NO3)4 (9) was synthesized from the precursor K[PtCl3(quin)] (1), while the benzothiazole complexes, [{cis-Pt(A)2(bztz)}2--(dach)](NO3)4 ((A)2=(NH3)2 (10) and (A)2=en (11)) were synthesized from the precursors cis-[Pt(A)2Cl(bztz)] ((A)2=(NH3)2 (7) and (A)2=en (8)). Their interactions with N-acetyltryptophan and a model pentapeptide (N-Ac-WLDSW-OH), modeled on the pentapeptide recognition sequence (FSDLW) of p53-mdm2 interaction, were examined by fluorescence spectroscopy. The dinuclear complexes were found to be significantly stronger at quenching the fluorescence of tryptophan than their mononuclear Pt-based analogues indicating stronger binding. Molecular modeling suggests a sandwich mode of binding, and the flexibility of the dinuclear motif can allow the design of more selective and stronger-binding complexes. Based on these results a further prototype, [{Pt(en)(9-EtGua)}2-H2N(CH2)6NH2]4+, incorporating the purine 9-ethylguanine (9-EtG) as a stacking moiety, was prepared which showed good cytotoxicity in A2780 and OsACL tumor cell lines.

• 出版日期2014-6