Combretastatin A-4 derived 5-(1-methyl-4-phenyl-imidazol-5-yl)indoles with superior cytotoxic and anti-vascular effects on chemoresistant cancer cells and tumors.
5-(1-Methyl-4-phenyl-imidazol-5-yl)indoles 5 were prepared and tested as analogs of the natural vascular-disrupting agent combretastatin A-4 (CA-4). The 3-bromo-4,5-dimethoxyphenyl derivative 5c was far more active than CA-4 with low nanomolar IC50 concentrations against multidrug-resistant KB-V1/Vbl cervix and MCF-7/Topo mamma carcinoma cells, and also against CA-4-resistant HT-29 colon carcinoma cells. While not interfering markedly with the polymerization of tubulin in vitro, indole 5c completely disrupted the microtubule cytoskeleton of cancer cells at low concentrations. It also destroyed real blood vessels, both in the chorioallantoic membrane (CAM) of fertilized chicken eggs and within tumor xenografts in mice, without harming embryo or mouse, respectively. Indole 5c was less toxic than CA-4 to endothelial cells, fibroblasts, and cardiomyocytes. In highly vascularized xenograft tumors 5c induced distinct discolorations and histological features typical of vascular-disrupting agents, such as disrupted vessel structures, hemorrhages, and extensive necrosis. In a first preliminary therapy trial, indole 5c retarded the growth of resistant xenograft tumors in mice. © 2016 Elsevier Science Ltd. All rights reserved.
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany.
Katharina
K
Mahal
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany.
Bernhard
B
Biersack
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany.
Sebastian
S
Schruefer
Department of Molecular Structural Biology, Georg-August-University Göttingen, 37077 Göttingen, Germany.
Marcus
M
Resch
Department of Molecular Structural Biology, Georg-August-University Göttingen, 37077 Göttingen, Germany.
Ralf
R
Ficner
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany. Electronic address: rainer.schobert@uni-bayreuth.de.
Rainer
R
Schobert
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle-Saale, Germany.
Thomas
T
Mueller
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001632:Bibenzyls / Q000737:chemistry*; D001808:Blood Vessels / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001632:Bibenzyls; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin
Anticancer drugs; Combretastatin A-4; Imidazole; Indole; Mouse tumor xenografts; Vascular-disrupting agents