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Anticancer Gold(III) Peptidomimetics: From Synthesis to in vitro and ex vivo Biological Evaluations
Author(s) -
Boscutti Giulia,
Nardon Chiara,
Marchiò Luciano,
Crisma Marco,
Biondi Barbara,
Dalzoppo Daniele,
Dalla Via Lisa,
Formaggio Fernando,
Casini Angela,
Fregona Dolores
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800098
Subject(s) - chemistry , stereochemistry , amino acid , cytotoxicity , ex vivo , cisplatin , in vivo , in vitro , biochemistry , biology , microbiology and biotechnology , chemotherapy , genetics
Five new Au III ‐peptidodithiocarbamato complexes of the type [Au III Br 2 (dtc‐AA 1 ‐AA 2 ‐OR] (in which AA 1 = N ‐methylglycine (Sar), l / d ‐Pro; AA 2 = l / d ‐Ala, α‐aminoisobutyric acid (Aib); R=O t Bu, triethylene glycol methyl ether), differing with regard to the amino acid sequence and/or the chiral amino acid configuration, were designed to enhance tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand toward two peptide transporters (namely PEPT1 and PEPT2), which are upregulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, one‐ and two‐dimensional NMR spectroscopy, FT‐IR, and UV/Vis spectrophotometry. 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 [non‐small‐cell lung carcinoma], MCF‐7 [breast cancer], A2780 [ovarian carcinoma], H1975 [non‐small‐cell lung carcinoma], H460 [large‐cell lung carcinoma], and A431 [human epidermoid carcinoma]) showed the dtc‐Pro‐Aib‐O t Bu derivative to be very effective, with GI 50 values much lower than those of cisplatin. This complex was thus selected for evaluating stability under physiological conditions and possible interactions with serum albumin, as well in PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues.