Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy.

Abstract

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 [Au(III)X(2)(dtc-Sar-L-Ser(t-Bu)-O(t-Bu))] (X=Br (1a)/Cl (1b)), [Au(III)X(2)(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)), [Au(III)X(2)(dtc-Sar-Aib(3)-O(t-Bu))] (X=Br (4a)/Cl (4b)), and [Au(III)X(2)(dtc-Sar-Aib(3)-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(III)Cl(2)(dtc-D,L-Pro-Aib(2)-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 IC(50) 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.

• Authors: Morelle Negom Kouodom, Giulia Boscutti, Marta Celegato, Marco Crisma, Sergio Sitran, Donatella Aldinucci, Fernando Formaggio, Luca Ronconi, Dolores Fregona
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 117 Pg. 248-60 (Dec 2012) ISSN: 1873-3344 [Electronic] United States
• PMID: 22877925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Organogold Compounds
• Peptidomimetics
• Thiocarbamates
• Gold
• Cisplatin
• Sarcosine

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cisplatin (chemistry)
• Coordination Complexes (chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Gold (chemistry)
• Humans
• Organogold Compounds (chemistry, pharmacology)
• Peptidomimetics (chemistry)
• Sarcosine (chemistry, pharmacology)
• Structure-Activity Relationship
• Thiocarbamates (chemistry, pharmacology)