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Kouodom M.N.,University of Padua | Boscutti G.,University of Padua | Celegato M.,Centro Of Riferimento Oncologico Cro Ircss | Crisma M.,CNR Institute of Neuroscience | And 5 more authors.
Journal of Inorganic Biochemistry | Year: 2012

As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato dtc derivatives of oligopeptides as potential anticancer agents, complexes [AuIIIX2(dtc-Sar-l-Ser(t-Bu)- O(t-Bu))] (X = Br (1a)/Cl (1b)), [AuIIIX2(dtc-AA-Aib 2-O(t-Bu))] (AA = Sar (sarcosine, N-methylglycine), X = Br (2a)/Cl (2b); AA = d,l-Pro, X = Br (3a)/Cl (3b)), [AuIIIX2(dtc- Sar-Aib3-O(t-Bu))] (X = Br (4a)/Cl (4b)), and [AuIIIX 2(dtc-Sar-Aib3-Gly-OEt)] (X = Br (5a)/Cl (5b)) (Aib = alpha-aminoisobutyric acid, 2-methylalanine) were designed to obtain metal-based peptidomimetics that may specifically target two peptide transporters (namely, PEPT1 and PEPT2) upregulated in several human tumor cells. All the compounds were characterized by means of FT-IR and mono- and multidimensional NMR spectroscopy. According to in vitro cytotoxicity studies, complex [Au IIICl2(dtc-d,l-Pro-Aib2-O(t-Bu))] (3b) turned out to be the most effective toward the four human tumor cell lines evaluated (PC3, 2008, C13, and L540), for which the IC50 values were lower than cisplatin. Remarkably, it showed no cross-resistance with cisplatin itself and was proved to inhibit tumor cell proliferation by inducing almost exclusively late apoptosis/necrosis. Biological results are here reported and discussed in terms of the structure-activity relationship. © 2012 Elsevier Inc. All rights reserved. Source


Boscutti G.,University of Padua | Feltrin L.,University of Padua | Lorenzon D.,Centro Of Riferimento Oncologico Cro Ircss | Sitran S.,University of Padua | And 3 more authors.
Inorganica Chimica Acta | Year: 2012

As a further extension of our research work focusing on the development of gold(III)-dithiocarbamato derivatives as potential anticancer agents, the new complexes [Au IIIX 2(dtc-Sar-O(t-Bu))] (X = Cl (1)/Br (2)) are here reported. The compounds were characterized by means of FT-IR, ESI mass, and mono- and multidimensional NMR spectroscopy. In order to get further insights into the possible behavior under physiological conditions, their affinity toward selected model biomolecules was spectroscopically investigated in detail. In this regard, they seem to react very slowly with isolated dAMP (but not dGMP), forming a species identified as [Au III(dtc-Sar-O(t- Bu))(dAMP-N 1,C 6NH)] +. In presence of GSH they undergo sudden reduction to the gold(I) counterpart [Au III 2(dtc-Sar-O(t-Bu)) 2], whereas only secondary interactions seem to occur when reacted with BSA. According to in vitro cytotoxicity studies, both complexes turned out to be highly effective toward all the human tumor cell lines evaluated (HeLa, L540 and U937), reporting IC 50 values lower than cisplatin. Apoptosis was proved a major cell death mechanism and, accordingly, DNA fragmentation was observed. Remarkably, cell cycle progression was negligibly affected, thus supporting the hypothesis of a different mechanism of action from clinically-established platinum-based drugs. © 2012 Elsevier B.V. All rights reserved. Source

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