Title
Anticancer gold(III) peptidomimetics: from synthesis to in vitro and ex vivo biological evaluation
Author
Giulia Boscutti, Chiara Nardon, Luciano Marchiò, Marco Crisma, Barbara Biondi, Daniele Dalzoppo, Lisa Dalla Via, Fernando Formaggio, Angela Casini, Dolores Fregona
Year
2018
Journal
ChemMedChem
Abstract
Five new Au(III)‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR] (AA1=Sar, L/D‐Pro; AA2=L/D‐Ala, Aib; R=OtBu, TEG), differing in the amino acidic sequence and/or the chiral amino acid configuration, were designed to enhance the tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand towards two peptide transporters (namely, PEPT1 and PEPT2), up‐regulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, mono‐ and bidimensional NMR spectroscopy, FT‐IR and UV‐Vis spectrophotometries. The crystal structures of three compounds were also solved by X‐ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549, MCF‐7, A2780, H1975, H460 and A431) showed that the dtc‐Pro‐Aib‐OtBu derivative is very effective, with GI50 values much lower than those of Cisplatin. It was thus selected for evaluating the stability under physiological conditions and possible interaction with serum albumin as well as for PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues.
Instrument
J-715
Keywords
Circular dichroism, Secondary structure, Chemical stability, Biochemistry, Pharmaceutical