• Ph.D., 2001, Tel Aviv University
• B.S., 1998, Hebrew University of Jerusalem
We are working on original topics in the general area of synthetic bioinorganic chemistry. We investigate biological phenomena that involve transition metal centers, either natural or synthetic, by applying coordination chemistry methodology. We thus combine metal chemistry with biological and medicinal procedures.
Early Transition Metal Complexes for Anti-Tumor Applications
Titanium(IV) and vanadium(V) complexes represent attractive alternatives to platinum-based anti-cancer drugs due to their wider activity range and reduced toxicity. Titanium is a biologically friendly metal; titanium dioxide is often found in food products and cosmetics, and is known to be a safe non-toxic material with no side-effects. Vanadium is also a naturally occurring element, which was previously implemented successfully in various therapeutics. The main drawback of both metals is their potentially rich aquatic chemistry and decomposition in biological environment. Thus, we produce hydrolytically stable titanium and vanadium compounds based on costume-designed ligands, and explore their medicinal applications.
The complexes developed in our laboratory rely on strongly binding phenolato ligands. Such complexes demonstrate substantially higher activity than those known compounds including cisplatin towards various cancer cells, with activity also toward drug-resistant cells and in vivo efficacy. Moreover, the strongly binding phenolato ligands afford particularly high stability for weeks in water, contributing further to the promise of these complexes. Various aspects of the complexes mechanism in the cells are under investigations, as well as structure activity studies to direct the design and development of improved derivatives.
Copper Complexes: Models for Copper Metallochaperones
Copper ions are essential for the well maintenance of living systems; however, their high redox activity may also lead to harmful formation of toxic radicals. Therefore, copper ions in biological environment are protected by binding proteins at all times, and metallochaperone proteins are responsible for copper trafficking in the cell. We are studying metallochaperone model complexes and their reactivity towards relevant oxygen-based species, inspired by the potential therapeutic application of a copper binding unit, with structural characteristics and redox reactivity similar to the natural system. Various model peptides analyzed exhibit unexpected structural motifs as well as promising in vitro anti-oxidative reactivity.
1. Ganot, N., Redko, B., Gellerman, G., and Tshuva, E. Y. (2015) Anti-proliferative Activity for the Combination of Salan Ti(IV) Complexes with other Organic and Inorganic Anticancer Drugs against HT-29 and NCL-H1229 Cells: Synergism with Cisplatin. RSC. Adv. 5:7874.
2. Meker, S., Margulis-Goshen, K., Weiss, E., Magdassi, S., and Tshuva, E. Y. (2012) High Antitumor Activity of Highly Resistant Salan–Titanium(IV) Complexes in Nanoparticles: An Identified Active Species. Angew. Chem. Int. Ed. 51:10515. Selected for Cover; Selected as "HOT PAPER”
3. Manna, C. M. , Braitbard, O. , Weiss, E. , Hochman, J. , and Tshuva, E. Y. (2012) Cytotoxic Salan-Titanium(IV) Complexes: High Activity Towards A Range of Sensitive and Drug Resistant Cell Lines and Mechanistic Insights. Chem. Med. Chem. 7:703.
4. Glasner, H. and Tshuva, E. Y. (2011) A Marked Synergistic Effect in Antitumor Activity of Salan Titanium(IV) Complexes Bearing Two Differently Substituted Aromatic Rings. J. Am. Chem. Soc. 133:16812
5. Shoshan, M. S., Shalev, D. E., Adriaens, W., Merkx, M. , Hackeng, T. M. and Tshuva, E. Y. (2011) NMR Characterization of a Cu(I)-Bound Peptide Model of Copper Metallochaperones: Insights on the Role of Methionine. Chem. Commun. 47: 6407
6. Peri, D., Meker, S., Shavit, M., and Tshuva, E. Y. (2009) Synthesis, Characterization, Cytotoxicity, and Hydrolytic Behavior of C2- and C1-Symmetrical Ti(IV) Complexes of Tetradentate Diamine Bis(phenolato) Ligands: A New Class of Anti-tumor Agents. Chem. Eur. J. 15:2403
7. Tshuva, E. Y. and Peri, D. (2009) Modern Cytotoxic Ti(IV) Complexes; Insights on the Enigmatic Involvement of Hydrolysis. Coord. Chem. Rev. 253:2098
8. Shavit, M., Peri, D., Manna, C. M., Alexander, J. S., and Tshuva, E. Y. (2007) Active Cytotoxic Reagents Based on Non-Metallocene Non-Diketonato Well-Defined C2-Symmetrical Titanium Complexes of Tetradentate Bis(phenolato) Ligands. J. Am. Chem. Soc. 129:12098.