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Forschungsarbeit

Gold(I) N-heterocyclic carbene complexes with ligands derived from the anti-vascular natural compound Combretastatin A-4 as new potential antitumor agents

by Julienne Münzner (26.05.2015)

Natural products frequently show biological activity that may be exploited for the treatment of various diseases [1,2]. Ancient documents reveal that plant extracts have already been used in Chinese medicine for thousands of years and also various indigenous cultures have largely employed herbal essences in their traditional medicinal rituals. Today, several plant-derived compounds have been approved for the treatment of cancer and/or served as lead structures for semi-synthetically optimized anticancer drugs.

The cis-stilbene combretastatin A-4 (CA-4) was first isolated from the bark of the South African Cape bush willow Combretum caffrum at the end of the 1980s [3]. Its better water-soluble prodrug CA-4P is currently in clinical trials and acts selectively on vascular endothelial cells leading to a so-called vascular shut-down in solid tumors [3-5]. This in turn results in a deprivation of oxygen and nutrients in the tumor and eventually in secondary tumor cell death. The pronounced anti-vascular activity of CA-4 is based on the inhibition of both tubulin polymerization and the VE-cadherin/β-catenin complex which is crucial for cell-cell adhesion. Various groups described heterocyclic derivatives of CA-4 that showed increased chemical stability while maintaining strong anti-vascular activity. As simple imidazolium salts have already been employed as ligand precursors for anticancer N-heterocyclic carbene (NHC) complexes, we prepared various gold(I) mono- and biscarbene complexes to combine the intrinsic anti-vascular activity of CA-4 analogous imidazoles with the anticancer properties of gold fragments [6-8].

[Bildunterschrift / Subline]: The natural vascular-disrupting agent combretastatin A-4 and examples of imidazolium salts and gold(I) NHC complexes derived from it.

Despite their lack of interaction with tubulin, the new gold (I) NHC complexes exhibit strong cytotoxic and anti-vascular effects, which are obviously based on a different mode of action. The gold(I) biscarbene complexes (L = NHC) are generally more efficacious than their corresponding monocarbene complexes (L = Cl or Br) showing IC50 values (72h) in the nanomolar range against several cancer cell lines. In 518A2 melanoma cells these complexes induced a distinct reorganization of the actin cytoskeleton so that sheaves of parallel F-actin filaments could be observed in treated cells unlike the cortical actin networks in control cells. This stress fiber formation is also most likely one reason for the strongly impaired motility of treated 518A2 cells. These results suggest a high anti-metastatic potential of the gold(I) NHC complexes.

[Bildunterschrift / Subline]: Figure 2: Effects of CA-4 derived gold(I) NHC complexes on blood vessels and cancer cells.

Additionally, treatment of melanoma cells with the biscarbene complexes (L = NHC) led to a significant accumulation of cells in the G1 phase of the cell cycle. This cell cycle arrest complements the other anticancer activities of the gold complexes mentioned above. We further investigated the anti-vascular activity of the gold(I) NHC complexes both in vitro by tube formation assays with human umbilical vein endothelial cells (HUVEC) and in vivo utilizing the chorioallantoic membrane (CAM) of fertilized chicken eggs. HUVEC have the ability to form networks of capillary like structures when grown on an extracellular matrix support.

We found that CA-4 derived gold complexes strongly inhibit the formation of these tubular structures and/or effectively destroy pre-formed capillary networks of HUVECs. Their vascular-disruptive activity could be further confirmed by in vivo CAM assays. Initial studies on the complexes’ in vivo effectiveness using mouse melanoma xenograft models revealed a good antitumoral activity of the gold(I) NHC complexes, while they were generally well tolerated by the mice.
Taken together, we could show that by combining NHC ligands, which are modelled on the bioactive combretastatin A-4 motif, with a gold(I) metal fragment also interacting with biomolecular targets, we can devise new complexes with “synergistic effects” originating from an interplay of both components.

 

References

[1] Mann, J. Natural products in cancer chemotherapy: past, present and future. Nat. Rev. Cancer 2002, 2, 143-148.
[2] Demain, A. L.; Vaishnav, P. Natural products for cancer chemotherapy. Microb. Biotechnol. 2011, 4, 687-699.
[3] Pettit, G. R.; Singh, S. B.; Hamel, E.; Lin, C.M.; Alberts, D. S.; Garcia-Kendall, D. Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989, 45, 209-211.
[4] Kanthou, C.; Tozer, G. M. The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells. Blood 2002, 99, 2060-2069.
[5] Vincent, L.; Kermani, P.; Young, L. M.; Cheng, J.; Zhang, F.; Shido, K.; Lam, G.; Bompais-Vincent, H.; Zhu, Z.; Hicklin, D. J.; Bohlen; P.; Chaplin, D. J.; May, C.; Rafii, S. Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J. Clin. Invest. 2005, 115, 2992-3006.
[6] Kaps, L.;, Biersack, B.; Müller-Bunz, H.; Mahal, K.; Münzner, J.; Tacke, M.; Mueller, T.; Schobert, R. J. Inorg. Biochem. 2012, 106, 52-58.
[7] Münzner, J.; Biersack, B.; Kaps, L.; Mahal, K.; Schobert, R.; Sasse, F. Synergistic "gold effects" of anti-vascular 4,5-diarylimidazol-2-ylidene gold(I) carbene complexes. Int J. Clin. Pharmacol. Ther. 2013, 51, 44-46.
[8] Muenzner, J. K.; Biersack, B.; Kalie, H.; Andronache, I. C.; Kaps, L.; Schuppan, D.; Sasse, F.; Schobert, R. Gold(I) biscarbene complexes derived from vascular-disrupting combretastatin A-4 address different targets and show antimetastatic potential. ChemMedChem. 2014, 9, 1195-1204.


Wissenschaftlicher Werdegang
  • seit 2014
  • Mitglied der „University of Bayreuth Graduate School“
  • seit 2011
  • Doktorandin, Universität Bayreuth, Organische Chemie I, Betreuer: Prof. Dr. Rainer Schobert
  • seit 2009
  • Studentin im Elitestudienprogramm „Macromolecular Science“ im Rahmen des Elitenetzwerks Bayern, Universität Bayreuth
  • 2009-2011
  • M.Sc. in Biochemie und Molekulare Biologie, Universität Bayreuth
  • 2006-2009
  • B.Sc. in Biochemie, Universität Bayreuth

Preise und Auszeichnungen
  • * Best Abstract Preis, CESAR (Central European Society for Anticancer Drug Research) Jahrestagung, Essen (2012)

Veröffentlichungen
  • * Muenzner J.K., Biersack B., ..., Schobert R. Gold(I) biscarbene complexes derived from vascular-disrupting combretastatin A-4 address different targets and show antimetastatic potential, ChemMedChem 2014, 9, 1195-1204
  • * Muenzner J., Biersack B., Kaps L., Schobert R., Sasse F. Synergistic "gold effects" of anti-vascular 4,5-diarylimidazol-2-ylidene gold(I) carbene complexes, Int. J. Clin. Pharmacol. Ther. 2013, 51, 44-46
  • * Kaps L., Biersack B., Müller-Bunz H., Mahal K., Münzner J., Tacke M., Mueller T., Schobert R. Gold(I)-NHC complexes of antitumoral diarylimidazoles: Structures, cellular uptake routes and anticancer activities, J. Inorg. Biochem. 2012, 106, 52-58.