Metal-based glycoconjugates and their potential in targeted anticancer chemotherapy

Glucose is a key source of energy and an essential nutrient for cell growth. Rapidly dividing cancer cells are well-known to require more nutrients and energy than normal ones to sustain their higher proliferation rates, and glucose is no exception. Therefore, the biomolecules involved in the promotion/regulation of the glycolytic flux may be regarded as potential targets for tackling tumor progression. Among all, glucose transporters (GLUTs), devoted to the recognition and cellular internalization of glucose, are largely overexpressed in tumors, thus indicating glycolysis as the major anaerobic glucose metabolism. Accordingly, such increased demand of glucose by fast-proliferating cancer cells makes it very attractive to selectively target tumor sites. In particular, tailored glucose-like substrates can be conjugated to chemotherapeutics (including metal-containing anticancer agents) so as to attain the site-specific delivery of drugs into the affected tissues. Progress in the development of metal-based glycoconjugates are here summarized and discussed.

Expanding on the Structural Diversity of Flavone- Derived RutheniumII(ƞ6-arene) Anticancer Agents

Abstract3-Hydroxyflavones belong to the naturally occurring class of flavonoids and have been extensively studied with regard to medicinal application. Moreover, it has been demonstrated that these compounds act as bioactive chelates to the ruthenium(II)–arene moiety. Such organometallic complexes have shown promising anticancer activity against tumor cells via a multitargeting mode of action, interacting with DNA and inhibiting topoisomerase IIα. In this paper, we present the synthesis and characterization of an extended series of 3-hydroxyflavone ligands and their corresponding ruthenium-p-cymene complexes to study the impact of substitution pattern as well as of electron-withdrawing and –donating substituents at the flavonol-phenyl group. The ligands and complexes were characterized by elemental analysis, ESI-MS, 1D as well as 2D NMR spectroscopy. The structures of four Ru(η6-p-cymene) complexes were determined in solid state by single-crystal X-ray diffraction, and the impact of the substitution pattern with regard to in vitro anticancer activity in human cancer cell lines is discussed. Structural differences, calculated octanol-water partition coefficients (clogP) of the flavonols and aqueous solubility were used to rationalize the finding that chlorido[3-(oxo-κO)-2-(3,5- dimethoxyphenyl)-chromen-4-onato-κO](η6-p-cymene)ruthenium(II) 2b exhibits the highest cytotoxicity with IC50 values in the low μM range in all tested cell lines.

From Traditional Drug Design to Catalytic Metallodrugs: A Brief History of the Use of Metals in Medicine

Traditional drug design has been effective in the development of therapies for a variety of disease states but there is a need for new approaches that will tackle new challenges and complement current paradigms. The use of metals in medicine has resulted in several successes and allows for the introduction of properties that cannot be achieved by use of organic compounds alone, but also introduces new challenges that can be addressed by a careful understanding of the principles of inorganic chemistry. Toward this end, the unique structural and coordination chemistry, as well as the reactivity of metals, has been used to design novel classes of therapeutic and diagnostic agents. This review briefly summarizes progress in the field of therapeutics, from the earliest use of metals to more recent efforts to design catalytic metallodrugs that promote the irreversible inactivation of therapeutically relevant targets.

Quantification of the titanium content in metallodrug-exposed tumor cells using HR-CS AAS

High-resolution continuum source atomic absorption spectroscopy (HR-CS AAS) is a valuable analytical technique for metal quantification because of its high sensitivity and selectivity for metal atoms as well as its improved background correction mode. However, the quantification of metals in biological materials, e.g. cell lysates, is still challenging because of matrix effects and other experimental complications. A method to quantify the titanium content of tumor cells exposed to titanium-based drugs was developed using HR-CS AAS. This method allows the quantification of titanium in cell suspensions in the low µg L