In Vitro and in Vivo Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tridentate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands

被引：107

作者：

Gandin, Valentina ^{[1
]}

Tisato, Francesco ^{[2
]}

Dolmella, Alessandro ^{[1
]}

Pellei, Maura ^{[3
]}

Santini, Carlo ^{[3
]}

Giorgetti, Marco ^{[4
]}

Marzano, Cristina ^{[1
]}

Porchia, Marina ^{[2
]}

机构：

[1] Univ Padua, Dipartimento Sci Farmaco, I-35131 Padua, Italy

[2] CNR, IENI, I-35127 Padua, Italy

[3] Univ Camerino, Scuola Sci & Tecnol, Sez Chim, I-62032 Camerino, Macerata, Italy

[4] Univ Bologna, Dipartimento Chim Ind, I-40136 Bologna, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 11期

关键词：

RAY-ABSORPTION SPECTROSCOPY; BODY DISTRIBUTION-FUNCTIONS; SCORPIONATE LIGANDS; BIOLOGICAL-ACTIVITY; CRYSTAL-STRUCTURE; CONDENSED MATTER; METAL-COMPLEXES; DERIVATIVES; POLY(PYRAZOLYL)BORATE; NITROIMIDAZOLE;

D O I：

10.1021/jm500279x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Tetrahedral copper(I) TpCuP complexes 1-15, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized by means of NMR, ESI-MS, and XAS-EXAFS, and X-ray diffraction analyses on the representative complexes 1 and 10, respectively. All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)(3)]Cu(PCN), 1, and [HB(pz)(3)]Cu(PTA), 2, showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of complex 1 was validated in the murine Lewis Lung Carcinoma (LLC) model.

引用

页码：4745 / 4760

页数：16

共 64 条

[1] A new ester substituted heteroscorpionate ligand [J].