Proceedings book download - 5Z.com

Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Targeted Platinum Peptide Complexes Holding Diamino andDicarboxylic Coordination ModesAgnieszka M. Glowinska 1 , Anna Lesniak 2 , Marzena Lazarczyk 2 ,Ewa Matyja 2 , Andrzej W. Lipkowski 2 , and Aleksandra Misicka 11 Faculty of Chemistry Warsaw University, Warsaw, 02-093, Poland; 2 Medical ResearchCentre Polish Academy of Science, Warsaw, 02-106, PolandIntroductionApplying biologically active carrier ligands into platinated drug moieties generatesa promising tool in anticancer therapy. Previously presented outcome [1] based on theopioid receptors’ overexpression at cancer cells [2], indicated a potential for selective drugdelivery, targeting malignant cells. Our idea was to reduce cisplatin drawbacks by use ofhybride-molecules combining two fragments. One part of the molecule contains the opioidpharmacophore and the other fragment is designed to form a complex with platinum ion[3]. As a result such molecule can serve not only as carrier for platinum but also give astrong analgesic effect with potential anticancer activity.Results and DiscussionSelective delivery of platinum moiety built into a multivalent complex was based onbifunctional structure design consisting of vector ligand and anticancer drug fragmentslinked by specific spacers (Figure 1). Promising antiproliferative properies (the proliferationT98G cells measured on the 4th day is 50% lower, compared to the control) andopioid receptor binding results (affinity at the opioid receptors in the nM range), obtainedfor the pioneer molecule (Table 1, compound 1) and demonstrated our structures aspotential model for anticancer drug design. Recently, we have focused on improvingcompound solubility and the separation distance of active fragments. Hydrophilic linkers(1-amino-4,7,10-trioxa-13-tridecaamide and 4,7,10-trioxa-1,13-tridecanediamine succinicacid monoamide [4]) were chosen to result in solubility enhancement. In addition,lipophilic spacer (1,3-propanediamine succinic acid monoamide) was selected to inducemembrane permeability. Ligands responsible for platinum ion coordination were dividedinto groups involving diamino (DAP, DAB), dicarboxylic (Glu) or mixed amino-carboxylictype (His). Diamino ligand type with chloro ions as leaving groups, were reported to beresponsible for effective DNA structure distortions defining carcinoma cell’s death. [5] Onthe other hand, decreased reactivity of carboxylate ions as leaving groups has been provedto diminish such interactions what resulted in reduced drug toxicity effect. We decided toimplement both modes of platinum ion chelation types in our bifunctional systems andverify how introduction of disparate ligand’s lability, platinum coordination type and linkercharacter may influence compound physical properties and bioactivity.ClOpioid peptideLinkerAA[X,Y]PtClVector ligandFig. 1. Multivalent complex components.FunctionalspacerLigand chelating Pt(II)354