Kidney cancer is among the most common cancers and prostate cancer is a major cause of morbidity and mortality in men in the US. There is a clear need to increase the number of chemotherapeutic options for these cancers to use alone or in combination with targeted agents. Metallo-drugs are important tools in current cancer therapy. Platinum-derived drugs, commonly used, have failed in renal and prostate cancers. Titanium-based drugs have high preclinical activity and hold potential for anticancer therapy, especially for metastatic renal, metastatic breast and prostate cancers. However, their mode of action remains unclear. Recent studies indicate that gold complexes also display considerable anti-tumor properties both in vitro and in vivo against cisplatin-resistant cancer cell lines with different mode of action than cisplatin itself. Preliminary results demonstrate that compounds containing both titanium and gold have significant anti-tumor properties in vitro against prostate cancer cell lines. The long-term goal of this proposal is to develop heterometallic titanium-gold anticancer chemotherapeutics for the treatment of renal and prostate cancers. Our hypothesis is that the incorporation of two different metals with anti-tumor properties in the same molecule will improve their activity due to: a) interaction of the different metals with multiple biological targts and b) improved chemicophysical properties of the heterometallic compound. We will synthesize new titanium organometallic compounds with phosphine-, and iminophosphorane-modified cyclopentadienyl (Cp) ligands able to further coordinate gold moieties. The anti-tumor properties and mechanism of action of the new titanium and titanium-gold derivatives prepared will be evaluated using different human kidney and prostate cancer cell lines.
Aim 1. To synthesise and to determine the stability, in vitro and in vivo anti-tumor activity of titanium and titanium-gold compounds with phosphine- and iminophosphorane-containing ligands.
Aim 2 : To test the hypothesis that the improved activity of titanium-gold compounds is due to their interactions with multiple biological targets. We will evaluate the interaction of these compounds with different biomolecular targets, including protein kinases, DNA, transport and mitochondrial proteins, and cell death pathways. This research will elucidate the mode of action of promising non-platinum anti-cancer heterometallic derivatives. The knowledge gained from the studies of the kinase inhibitory properties of these compounds will guide the design of more selective or targeted chemotherapeutics for treating humans in the future. We will work in collaboration with Prof. Ramos (University of Hawaii Cancer Center).

Public Health Relevance

Kidney cancer is among the 10 most common cancers in both men and women, and prostate cancer is a major cause of morbidity and mortality in men in the US. Due to clinical problems associated with the drugs currently used in treatment therapies, there is a clear need to increase the number of chemotherapeutic options for renal and prostate cancers. The proposed studies are relevant to public health as they will help to design new anticancer pharmaceuticals for renal and prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
4SC1CA182844-04
Application #
9089601
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Chung, Davyd W
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brooklyn College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
620127691
City
New York
State
NY
Country
United States
Zip Code
11210
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de la Cueva-Alique, Isabel; Muñoz-Moreno, Laura; Benabdelouahab, Yosra et al. (2016) Novel enantiopure cyclopentadienyl Ti(IV) oximato compounds as potential anticancer agents. J Inorg Biochem 156:22-34
Mui, Yiu Fung; Fernández-Gallardo, Jacob; Elie, Benelita T et al. (2016) Titanocene-Gold Complexes Containing N-Heterocyclic Carbene Ligands Inhibit Growth of Prostate, Renal, and Colon Cancers in Vitro. Organometallics 35:1218-1227
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Fernández-Gallardo, Jacob; Elie, Benelita T; Sadhukha, Tanmoy et al. (2015) Heterometallic titanium-gold complexes inhibit renal cancer cells in vitro and in vivo. Chem Sci 6:5269-5283
Benabdelouahab, Yosra; Muñoz-Moreno, Laura; Frik, Malgorzata et al. (2015) Hydrogen bonding and anticancer properties of water-soluble chiral p-cymene Ru(II) compounds with amino-oxime ligands. Eur J Inorg Chem 2015:2295-2307
Frik, Malgorzata; Fernández-Gallardo, Jacob; Gonzalo, Oscar et al. (2015) Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties. J Med Chem 58:5825-41
Massai, Lara; Fernández-Gallardo, Jacob; Guerri, Annalisa et al. (2015) Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents. Dalton Trans 44:11067-76
Frik, Malgorzata; Jiménez, Josefina; Vasilevski, Vadim et al. (2014) Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents. Inorg Chem Front 1:231-241

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