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The phosphorylation and dephosphorylation of proteins and other intracellular molecules are important reactions in living systems and are generally controlled by the action of kinases and phosphatases. The design and synthesis of artificial mimics of natural enzymes are important research subjects in bioorganic and bioinorganic chemistry. A supramolecular strategy based on the three-dimensional self-assembly of molecular building blocks would be useful for the construction of artificial supramolecular complexes. The main focus of this review is on artificial mimics of natural phosphatases that contain dimetallic cores in their active sites. Previous examples of artificial mimics of alkaline phosphatases (AP) constructed covalently are initially presented, then followed by a description of artificial metallosupramolecular complexes formed by the combinatorial self-assembly of different bis(Zn2+-cyclen) complexes containing 2,2′-bipyridyl (bpy) linker (cyclen = 1,4,7,10-tetraazacyclododecane), cyanuric acid or barbital (Bar) units, and Cu2+ ion in single or two-phase solvent systems. It is now thought that the appropriate combination of the various building blocks and solvent systems (single- and two-phase solvent systems) can strongly assist in developing the artificial systems that accelerate and catalyze the hydrolysis of a phosphate monoester, mono(p-nitrophenyl) phosphate (MNP). Such approaches would be useful in terms of understanding the mechanism of action of naturally occurring enzymes and to develop biologically active, bioorthogonal, and versatile supramolecular catalysts.

Death receptors (DR4 and DR5) offer attractive targets for cancer treatment because cancer cell death can be induced by apoptotic signal upon binding of death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with death receptors. Cyclometalated iridium(III) complexes such as fac-Ir(tpy)3 (tpy = 2-(4-tolyl)pyridine) possess a C3-symmetric structure like TRAIL and exhibit excellent luminescence properties. Therefore, cyclometalated Ir complexes functionalized with DR-binding peptide motifs would be potent TRAIL mimics to detect cancer cells and induce their cell death. In this study, we report on the design and synthesis of C3-symmetric and luminescent Ir complex-peptide hybrids (IPHs), which possess cyclic peptide that had been reported to bind DR5. The results of 27 MHz quartz-crystal microbalance (QCM) measurements of DR5 with IPHs and costaining experiments of IPHs and anti-DR5 antibody, suggest that IPHs bind with DR5 and undergo internalization into cytoplasm, possibly via endocytosis. It was also found that IPHs induce slow cell death of these cancer cells in a parallel manner to the DR5 expression level. These results indicate that IPHs may offer a promising tool as artificial luminescent mimics of death ligands to develop a new category of anticancer agents that detect and kill cancer cells.

We previously reported on the preparation of supramolecular complexes by the 2:2:2 assembly of a dinuclear Zn2+-cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) complex having a 2,2′-bipyridyl linker equipped with 0~2 long alkyl chains (Zn2L1~Zn2L3), 5,5-diethylbarbituric acid (Bar) derivatives, and a copper(II) ion (Cu2+) in aqueous solution and two-phase solvent systems and their phosphatase activities for the hydrolysis of mono(4-nitrophenyl) phosphate (MNP). These supermolecules contain Cu2(μ-OH)2 core that mimics the active site of alkaline phosphatase (AP), and one of the ethyl groups of the barbital moiety is located in close proximity to the Cu2(μ-OH)2 core. The generally accepted knowledge that the amino acids around the metal center in the active site of AP play important roles in its hydrolytic activity inspired us to modify the side chain of Bar with various functional groups in an attempt to mimic the active site of AP in the artificial system, especially in two-phase solvent system. In this paper, we report on the design and synthesis of new supramolecular complexes that are prepared by the combined use of bis(Zn2+-cyclen) complexes (Zn2L1, Zn2L2, and Zn2L3), Cu2+, and Bar derivatives containing amino acid residues. We present successful formation of these artificial AP mimics with respect to the kinetics of the MNP hydrolysis obeying Michaelis−Menten scheme in aqueous solution and a two-phase solvent system and to the mode of the product inhibition by inorganic phosphate.

The design and synthesis of some cyclometalated iridium(III) complexes containing quinoline-type ligands as ancillary ligands are reported. The emission spectra of Ir(III) complexes containing a quinolinolate (6, 8, 10) moiety exhibit a single emission peak at ca. 590 nm, resulting in a red colored emission. However, Ir(III) complexes containing 8-sulfonamidoquinoline ligands (11, 13-21) exhibit two different emission peaks (dual emission) at ca. 500 nm and ca. 600 nm upon excitation at 366 nm, resulting in a red-colored emission for 11 and a pale yellow-colored emission for 14-18 at 298 K. Especially, a white emission was observed for 19 at 298 and 77 K in dimethyl sulfoxide. The mechanistic studies based on time-dependent density functional theory calculations and time-resolved emission spectroscopy suggest that this dual emission originates from two independent emission states. [ABSTRACT FROM AUTHOR]

Cyclometalated iridium(III) complexes, because of their photophysical properties, have the potential for use as luminescent probes for cellular imaging. We previously reported on a pH-activatable iridium complex that contains three N,N-diethylamino groups, namely, fac-Ir(deatpy)3 5, which was synthesized via a regioselective aromatic substitution reaction at the 5'-position with tolylpyridine groups of fac-Ir(tpy)3 2. It was found that 5 shows a considerable enhancement in emission intensity in the pH range from neutral to slightly acidic (pH 6.5-7.4) in aqueous solution and selectively stains lysosome in HeLa-S3 cells, due to the protonation of the diethylamino groups. In addition, 5 functions as a pH-dependent singlet oxygen (¹O2) generator and induces necrosis-like cell death. However, observing the green emission of 5 is often hampered by autofluorescence emanating from nearby tissues. To overcome this problem, we designed and synthesized a series of new pH-activatable Ir(III) complexes that contain diethylamino, guanidyl, and iminoimidazolidinyl groups on the mpiq ligand of Ir(mpiq)3 7 and the tfpiq ligand of Ir(tfpiq)3 8, which exhibit a red emission, namely, Ir(deampiq)3 13, Ir(gmpiq)3 14, Ir(imzmpiq)3 15, and Ir(imztfpiq)3 16. The emission intensity of these Ir complexes is enhanced substantially by protonation of their basic groups, and they induce the necrosis-like cell death of HeLa-S3 cells by photoirradiation at 465 nm. A strong orange-red emission of Ir(mpiq-NO2)3 9 and Ir(tfpiq-NO2)3 10 is also reported. [ABSTRACT FROM AUTHOR]

A new DDAA hydrogen-bonding module (UImp-2), based on a ureidoimidazo[1,2-a]pyrimidine structure, forms a highly stable homodimer (Kdim> 1.1 × 105M−1in CDCl3) without competition from undesired hydrogen-bonded dimers. [ABSTRACT FROM AUTHOR]