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

Morelle Negom Kouodom, Giulia Boscutti, Marta Celegato, Marco Crisma, Sergio Sitran, Donatella Aldinucci, Fernando Formaggio, Luca Ronconi, Dolores Fregona

Research output: Contribution to journalArticle

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 [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.

Original languageEnglish
Pages (from-to)248-260
Number of pages13
JournalJournal of Inorganic Biochemistry
Volume117
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Sarcosine
Peptidomimetics
Chemotherapy
Gold
Cisplatin
Tumors
Drug Therapy
Oligopeptides
Structure-Activity Relationship
Tumor Cell Line
Cells
Antineoplastic Agents
Inhibitory Concentration 50
Neoplasms
Necrosis
Magnetic Resonance Spectroscopy
Metals
Cell Proliferation
Cell proliferation
Cytotoxicity

Keywords

  • Anticancer activity
  • Dithiocarbamates
  • Drug delivery
  • Gold
  • Peptide transporters (PEPTs)
  • Peptidomimetics

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy. / Kouodom, Morelle Negom; Boscutti, Giulia; Celegato, Marta; Crisma, Marco; Sitran, Sergio; Aldinucci, Donatella; Formaggio, Fernando; Ronconi, Luca; Fregona, Dolores.

In: Journal of Inorganic Biochemistry, Vol. 117, 12.2012, p. 248-260.

Research output: Contribution to journalArticle

Kouodom, MN, Boscutti, G, Celegato, M, Crisma, M, Sitran, S, Aldinucci, D, Formaggio, F, Ronconi, L & Fregona, D 2012, 'Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy', Journal of Inorganic Biochemistry, vol. 117, pp. 248-260. https://doi.org/10.1016/j.jinorgbio.2012.07.001
Kouodom, Morelle Negom ; Boscutti, Giulia ; Celegato, Marta ; Crisma, Marco ; Sitran, Sergio ; Aldinucci, Donatella ; Formaggio, Fernando ; Ronconi, Luca ; Fregona, Dolores. / Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy. In: Journal of Inorganic Biochemistry. 2012 ; Vol. 117. pp. 248-260.
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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 [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.",
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AU - Crisma, Marco

AU - Sitran, Sergio

AU - Aldinucci, Donatella

AU - Formaggio, Fernando

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AB - 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.

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