Titanium-gold-based chemotherapeutics for prostate and kidney cancer

描述（由申请人提供）：肾癌是最常见的癌症之一，前列腺癌是美国男性发病和死亡的主要原因。显然需要增加这些癌症的化疗选择的数量，以单独使用或与靶向药物联合使用。金属药物是当前癌症治疗的重要工具。常用的铂衍生药物在肾癌和前列腺癌治疗中失败了。钛基药物具有很高的临床前活性，具有抗癌治疗的潜力，特别是对于转移性肾癌、转移性乳腺癌和前列腺癌。然而，他们的行动方式仍不清楚。最近的研究表明，金配合物在体外和体内对顺铂耐药的癌细胞系也表现出相当大的抗肿瘤特性，其作用方式与顺铂本身不同。初步结果表明，含有钛和金的化合物在体外对前列腺癌细胞系具有显着的抗肿瘤特性。该提案的长期目标是开发异金属钛金抗癌化疗药物用于治疗肾癌和前列腺癌。我们的假设是，将两种具有抗肿瘤特性的不同金属掺入同一分子中将 由于以下原因提高了它们的活性：a）不同金属与多种生物靶标的相互作用；b）改善了异金属化合物的化学物理性质。我们将合成具有膦和亚氨基正膦修饰的环戊二烯基 (Cp) 配体的新型钛有机金属化合物，这些配体能够进一步配位金部分。所制备的新型钛和钛金衍生物的抗肿瘤特性和作用机制将使用不同的人肾癌细胞系和前列腺癌细胞系进行评估。目的 1. 合成含膦和亚氨基正膦配体的钛和钛金化合物，并测定其稳定性、体外和体内抗肿瘤活性。目标 2：检验钛金化合物活性提高是由于其与多个生物靶标相互作用所致的假设。我们将评估这些化合物与不同生物分子靶标的相互作用，包括蛋白激酶、DNA、转运蛋白和线粒体蛋白以及细胞死亡途径。这项研究将阐明有前途的非铂抗癌异金属衍生物的作用模式。从这些化合物的激酶抑制特性研究中获得的知识将指导未来治疗人类的更具选择性或针对性的化疗药物的设计。我们将与拉莫斯教授（夏威夷大学癌症中心）合作。

DESCRIPTION (provided by applicant): 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).