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Gold(I) Biscarbene Complexes Derived from Vascular‐Disrupting Combretastatin A‐4 Address Different Targets and Show Antimetastatic Potential
Author(s) -
Muenzner Julienne K.,
Biersack Bernhard,
Kalie Hussein,
Andronache Ion C.,
Kaps Leonard,
Schuppan Detlef,
Sasse Florenz,
Schobert Rainer
Publication year - 2014
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.201400049
Subject(s) - combretastatin , in vivo , cancer research , chemistry , umbilical vein , chorioallantoic membrane , in vitro , cell cycle checkpoint , cell culture , cancer cell , melanoma , endothelial stem cell , microbiology and biotechnology , cell cycle , tubulin , cell , cancer , biology , microtubule , biochemistry , medicine , genetics
Gold N ‐heterocyclic carbene (NHC) complexes are an emerging class of anticancer drugs. We present a series of gold(I) biscarbene complexes with NHC ligands derived from the plant metabolite combretastatin A‐4 (CA‐4) that retain its vascular‐disrupting effect, yet address different cellular and protein targets. Unlike CA‐4, these complexes did not interfere with tubulin, but with the actin cytoskeleton of endothelial and cancer cells. For the highly metastatic 518A2 melanoma cell line this effect was accompanied by a marked accumulation of cells in the G 1 phase of the cell cycle and a suppression of active prometastatic matrix metalloproteinase‐2. Despite these mechanistic differences the complexes were as strongly antivascular as CA‐4 both in vitro in tube formation assays with human umbilical vein endothelial cells, and in vivo as to blood vessel disruption in the chorioallantoic membrane of chicken eggs. The antiproliferative effect of the new gold biscarbene complexes in a panel of six human cancer cell lines was impressive, with low sub‐micromolar IC 50 values (72 h) even against CA‐4‐refractory HT‐29 colon and multidrug‐resistant MCF‐7 breast carcinoma cells. In preliminary studies with a mouse melanoma xenograft model the complexes led to significant decreases in tumor volume while being very well tolerated.