title: Dinuclear platinum complexes containing planar aromatic ligands to enhance stacking interactions with proteins.
abstract: In an approach to design drugs with higher affinity for π-π stacking and electrostatic interactions with targeted biomolecules, complexes of the type [{cis-Pt(A)2 (L)}2 -μ-{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 -μ-(dach)](NO3 )4 (9) was synthesized from the precursor K[PtCl3 (quin)] (1), while the benzothiazole complexes, [{cis-Pt(A)2 (bztz)}2 -μ-(dach)](NO3 )4 ((A)2 =(NH3 )2 (10) and (A)2 =en (11)) were synthesized from the precursors cis-[Pt(A)2 Cl(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 μ-H2 N(CH2 )6 NH2 ](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.
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-2006 (USA).
authors.forename: Erin S F
authors.initials: ES
authors.lastname: Ma
authors.forename: A Gerard
authors.initials: AG
authors.lastname: Daniel
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D000595:Amino Acid Sequence; D052160:Benzothiazoles / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; D056831:Coordination Complexes; D008024:Ligands; D010455:Peptides; D011804:Quinolines; D016159:Tumor Suppressor Protein p53; C006392:N-acetyltryptophan; D010984:Platinum; D014364:Tryptophan; C037219:quinoline; D051736:Proto-Oncogene Proteins c-mdm2; C005465:benzothiazole
keywords: heterocycles; platinum; protein recognition; tryptophan; π-π stacking