Biomedical and biochemical applications of self-assembled metallacycles and metallacages.

Metal ions and metal complexes with organic molecules are ubiquitous in nature. Bulk metal ions of Na, K, Mg, and Ca constitute as much as 1% of human body weight. The remaining trace ions, most commonly of Fe, Ni, Cu, Mn, Zn, Co, Mo, and V, make up ∼0.01% by weight, but their importance in biological processes cannot be overstated. Although nature is limited to the use of bioavailable metal ions, many rarer transition metals can elicit novel biological responses when they interact with biomolecules. For this reason, metal-biomolecule complexes are of interest in medicinal applications. A well-known example is cisplatin, which contains Pt, rare in nature, but highly effective in this context as an anticancer drug in the form of cis-Pt(NH3)2Cl2 and analogous Pt(II) complexes. This and other examples have led to strong interest in discovering new metalloanticancer drugs. In this Account, we describe recent developments in this area, particularly, using coordination-driven self-assembly to form tunable supramolecular coordination complexes (SCCs) with biomedical applications. Coordination-driven self-assembly describes the spontaneous formation of metal-ligand bonds in solution, transforming molecular building blocks into single, 2D metallacycles, or 3D metallacages depending on the directionality of the precursors used. Such SCCs have well-defined internal cavities and simple pre- or post-self-assembly functionalizations. They are highly tunable both spatially and electronically. Metal ions are necessary structural elements for the directional bonding approach, which can be exploited to provide biological activity to an SCC, particularly for Pt- and Ru-based structures. Since these two metals are not only among the most commonly used for coordination-driven self-assembly but are also the basis for a number of small molecule anticancer agents, researchers have evaluated a growing number of SCCs for their antitumor properties. The biological application of SCCs is still an emergent field of study, but the examples discussed in this Account confirm that supramolecular scaffolds have relevance to a wide variety of biochemical and biomedical targets. SCCs can serve as anticancer agents, act as selective sensors for biologically important analytes, or interact with DNA and proteins. The myriad of possible SCCs and their almost limitless modularity and tunability without significant synthetic penalty suggests that the biological applications of such species will continue along this already promising path.

Growth Inhibitory Activity of a Bis-benzimidazole-Bridged Arene Ruthenium Metalla-Rectangle and Prism.

Two new supramolecular coordination complexes (SCCs), were obtained from the self-assembly of a new bis-benzimidazole bridged Ru acceptor, 4, with dipyridyl and tripyridyl donors, respectively. As part of a growing library of anticancer-active Ru-based SCCs, metalla-prism 6 selectively showed high cytotoxicities relative to cisplatin for a series of cancer cell lines, with IC50 values as low as 8.41 µM for MCF7 cells, as determined from MTS assays.

Self-assembly of ambidentate pyridyl-carboxylate ligands with octahedral ruthenium metal centers: self-selection for a single-linkage isomer and anticancer-potency studies.

The synthesis of six new [2+2] metallarectangles through the coordination-driven self-assembly of octahedral Ru(II)-based acceptors with ambidentate pyridyl-carboxylate donors is described. These molecular rectangles are fully characterized by (1)H NMR spectroscopy, high-resolution electrospray mass spectrometry, and single-crystal X-ray diffraction. In each case, despite the possible formation of multiple isomers, based on the relative orientation of the pyridyl and carboxylate groups (head-to-head versus head-to-tail), evidence for the formation of a single preferred ensemble (head-to-tail) was found in the (1)H NMR spectra. Furthermore, the cytotoxicities of all of the rectangles were established against A549 (lung), AGS (gastric), HCT-15 (colon), and SK hep 1 (liver) human cancer cell lines. The cytotoxicities of rectangles that contained the 5,8-dihydroxy-1,4-naphthaquinonato bridging moiety between the Ru centers (9-11) were particularly high against AGS cancer cells, with IC50 values that were comparable to that of reference drug cisplatin.

Self-assembled metalla-rectangles bearing azodipyridyl ligands: synthesis, characterization and antitumor activity.

Sixteen arene-Ru based molecular-rectangles were self-assembled in high yields by the equimolar mixing of arene-Ru acceptors (Aa-Ad) with various azopyridyl ligands (1,2-di(pyridyl-4yl)diazene (L1), 1,2-bis(pyridin-4-ylmethylene)hydrazine (L2), 1,2-bis(1-(pyridin-4-yl)ethylidene)hydrazine (L3), 1,2-bis(pyridin-4-ylmethylene)hydrazine (L4)) in nitromethane-methanol solutions. These new molecular-rectangles were fully characterized by a host of analytical techniques including elemental analysis, (1)H and (13)C NMR and HR-ESI-MS. The solid-state structures of two molecular-rectangles (1b and 4d) were determined by single crystal X-ray diffraction data. UV-visible and fluorescence studies were also carried out for the entire suite of rectangles. As with recent studies of similar arene-Ru complexes, the anti-proliferative activities of these complexes were evaluated against SK-hep-1 (liver cancer) and A-549 (lung cancer) human cancer lines. Additionally, the cellular pharmacology and intracellular localizations in AGS (gastric cancer) human cancer cells were determined for selected complexes (1c, 1d and 4c) by apoptosis and fluorescence microscopy studies. These studies confirm that arene-Ru molecular-rectangles inhibit cell cycle progression to the G0 phase, in contrast to that of cisplatin which arrests cell growth in the G2 phase.

Coordination-driven self-assembly of ruthenium-based molecular-rectangles: synthesis, characterization, photo-physical and anticancer potency studies.

A suite of eight cationic, tetra-metallic molecular rectangles (1-8) was generated via coordination-driven self-assembly using four dicarboxylate-bridged arene-Ru precursors (A1-A4) with one of two dipyridyl ligands (D1, D2). The high-yielding (84-92%) rectangles were characterized by (1)H NMR and HR-ESI-MS to support their structural assignments. The molecular structure of 5 was determined by single crystal X-ray analysis, which indicated that two D2 ligands bridge two A1 acceptors to form a rectangular construct. The photophysical properties of these metalla-rectangles and their molecular precursors were also investigated, as well as an MTT assay to evaluate the in vitro cytotoxicities relative to two chemotherapeutic agents, cisplatin and doxorubicin. MTT assays were conducted using SK-hep-1 (liver cancer) and HCT-15 (colon cancer) human cancer cell lines. Compounds 3, 4, 7 and 8 showed significant activity, with IC(50) values comparable to those of cisplatin and doxorubicin.

Self-assembly of Cationic, Hetero- or Homo-nuclear Ru(II) Macrocyclic Rectangles and their Photophysical, Electrochemical and Biological Studies.

A series of supramolecular rectangles, including two mixed-metal Ru/Pt complexes, have been formed by the coordination-driven self-assembly of a range of arene-Ru "molecular clip" acceptors (1a-1d) with rigid dipyridyl-based ligands (2a-2d) over the course of 10 hours in solution. The isolated products were characterized by multinuclear NMR ((1)H and (13)C or (31)P), HR-ESI-MS and an X-ray diffraction study to support the ascribed two-component rectangular structures. The rectangles were further characterized by UV-Vis and fluorescence studies. The redox behaviors of rectangles 3ca and 3da were also determined using cyclic voltammetry. Additionally, the antitumor activities of the suite of rectangles were determined against various human cancer cell lines and significant activity was shown by complexes 3ca, 3da, 3cb, 3cc and 3cd, with IC(50) values as low as 2.65 µM.

Coordination Driven Self-Assembly and Anticancer Activity of Molecular Rectangles Containing Octahedral Ruthenium Metal Centers.

The synthesis of new 2+2 metalla-rectangles via coordination driven self-assembly of octahedral Ru(II) based acceptors and amide donors is described. To evaluate their in vitro cytotoxic properties, preliminary biological assays were carried out for various human cancer cell lines, and our results show that the cytotoxicity level of 3 is comparable or even greater in the cases of SK-hep-1 and HCT-15 than that of the reference drug cisplatin.

Hexanuclear self-assembled arene-ruthenium nano-prismatic cages: potential anticancer agents.

Two novel nano-cage compounds, 8 and 9, were prepared by self-assembly of the ruthenium complexes 4 and 5, and the tripodal donor 1. The cytotoxicity of 8 was found to be considerably stronger than that of cisplatin. The complex 8 inhibited tumor cell proliferation by interfering into regulatory pathways of the cell cycle via apoptosis.