Dong-Gyu Cho

Modern reaction-based indicator systems

Traditional analyte-specific synthetic receptors or sensors have been developed on the basis of supramolecular interactions (e.g., hydrogen bonding, electrostatics, weak coordinative bonds). Unfortunately, this approach is often subject to limitations. As a result, increasing attention within the chemical sensor community is turning to the use of analyte-specific molecular indicators, wherein substrate-triggered reactions are used to signal the presence of a given analyte. This tutorial review highlights recent reaction-based indicator systems that have been used to detect selected anions, cations, reactive oxygen species, and neutral substrates.

The Benzil−Cyanide Reaction and Its Application to the Development of a Selective Cyanide Anion Indicator

The benzil-cyanide reaction is a cyanide-specific reaction that has been exploited to produce a colorimetric indicator for this toxic anion. This was done by producing a pi-extended analogue of benzil, 7, which is soluble in a 70:30 (v/v) mixture of methanol-water. In this medium, dilute solutions of 7 are yellow but produce colorless products when exposed to low concentrations of cyanide anion (> or = 1.7 microM; added as an aqueous NaCN solution), but no other common anions (e.g., OH(-), F(-), N3(-), benzoate(-), and H2PO4(-)). On the basis of these observations and supporting mechanistic analyses, it is concluded that the modified benzil system 7 is a promising cyanide anion indicator that is attractive in terms of its selectivity, ease-of-use, water compatibility, and the low, naked-eye discernible cyanide detection limit it provides.

Nonlinear optical properties as a guide to aromaticity in congeneric pentapyrrolic expanded porphyrins: pentaphyrin, sapphyrin, isosmaragdyrin, and orangarin.

On the basis of two-photon absorption and time-resolved spectroscopic measurements, as supported by theoretical calculations of quantitative aromaticity, a relationship between the nonlinear optical properties and aromaticity index has been established for a series of four fully conjugated pentapyrrolic expanded porphyrins, namely pentaphyrin (1.1.1.1.1), sapphyrin (1.1.1.1.0), isosmaragdyrin (1.1.1.0.0), and orangarin (1.0.1.0.0), all of which proved amenable to study in dichloromethane.

N-Tosylpyrrolidine calix[4]pyrrole: synthesis and ion binding studies.

The synthesis and preliminary solution phase ion binding properties of the N-tosylpyrrolidine calix[4]pyrrole 2 are reported. This β-octaalkyl-substituted calix[4]pyrrole, the first to be prepared via a direct condensation reaction, was obtained by reacting the 3,4-alkyl-functionalized pyrrole 8 with acetone in the presence of an acid catalyst. On the basis of (1)H NMR spectroscopic analyses and isothermal titration calorimetry, it was concluded that, compared with the parent, β-unsubstituted calix[4]pyrrole (1), compound 2 possesses significantly enhanced binding ability for halide anions in chloroform. Furthermore, 2 proved capable of solubilizing in chloroform solution the otherwise insoluble salts, CsF and CsCl. These effects are ascribed to the interactions between the four tosyl groups present in 2 and the counter cations of the halide anion salts.

Sapphyrins induce apoptosis in hematopoietic tumor-derived cell lines and show in vivo antitumor activity

Sapphyrins are pentapyrrolic, metal-free, expanded porphyrins. In the present study, the activity of sapphyrins as anticancer agents in hematopoietic-derived tumor cells was explored. It was found that a dihydroxylated water-soluble sapphyrin derivative (PCI-2000) is a potent inducer of apoptosis in a wide variety of tumor cell lines including lymphoma (Ramos, DHL-4, and HF-1), leukemia (Jurkat and HL-60), and myeloma (8226/S, 1-310, C2E3, and 1-414). PCI-2000 triggers an apoptotic pathway in these tumor cells as shown by release of cytochrome c from mitochondria; activation of caspases 9, 8, and 3; cleavage of the caspase substrate poly(ADP-ribose) polymerase; and Annexin V binding. Apoptosis can be partially inhibited by overexpression of the antiapoptotic protein Bcl-2 or treatment with benzyloxycarbonyl-valine-alanine-aspartic acid-fluoromethylketone, a cell-permeable caspase inhibitor. Both PCI-2000 and PCI-2010, a tetrahydroxy bis-carbamate derivative of PCI-2000, result in increased levels of phosphorylated p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase phosphorylation resulted in a synergistic increase of PCI-2000 cytotoxicity. PCI-2010 showed less toxicity in mice than PCI-2000 and was active in slowing the growth of Ramos and HL-60 tumor xenografts in nude mice. These results provide preclinical rationale for the further study of sapphyrins for potential use in the treatment of hematopoietic-derived tumors.

Hg(II)-mediated intramolecular cyclization reaction in aqueous media and its application as Hg(II) selective indicator.

The Hg(II)-specific intramolecular cyclization reaction of ethynyl phenols was carried out for the first time in semiaqueous media at ambient temperature. The reaction unit (ethynyl phenol) was coupled with a malononitrile derivative (signal unit), which afforded the chromogenic Hg(II) indicator 7. The reaction of the chromogenic Hg(II) indicator 7 was further optimized in DMSO/water (3:7, v/v) (10 mM PBS buffer, pH = 7.0). Compound 7 displays a color change from blue to pale yellow in the presence of Hg(II).

Dioxabenzosapphyrin: a new benzodifuran-derived sapphyrin analogue.

The synthesis and characterization of a new sapphyrin analogue, dioxabenzosapphyrin, are reported. The benzodifuran moiety upon which this system is based leads to the incorporation of two oxygen atoms within the central macrocyclic core, thus replacing two protonated nitrogen centers found in normal pentaaza sapphyrin derivatives, including those derived from benzodipyrroles. As expected, the loss of these two NH hydrogen bond donor sites greatly reduces the anion affinity for the diprotonated form, even though the overall charge is the same as in the corresponding sapphyrins. Interestingly, dioxabenzosapphyrin, but not the corresponding all-aza systems, is found to bind neutral guests, such as phenol and 4-nitrophenol, albeit weakly. This latter finding highlights a potentially new application for core-modified expanded porphyrin derivatives, namely, as receptors for hydrogen bond donating neutral substrates.

Tumor localization and antitumor efficacy of novel sapphyrin compounds

Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry–based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure–activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability. [Mol Cancer Ther 2006;5(11):2798–805]

Bis-ureidoquinoline as a selective fluoride anion sensor through hydrogen-bond interactions.

Bis-ureidoquinoline shows a characteristic UV-vis absorbance and turn-on fluorescence changes in the presence of the fluoride anion. Such selective changes probably originate from the hydrogen-bond interactions, as shown by the (1)H NMR titration and DFT calculations. Bis-ureidoquinoline can be used as a fluoride-selective sensor for the detection of fluoride anions under illumination from a laboratory hand-held UV lamp.

Conformationally Locked Tolans, β-Sheet Structures, and Photophysical Properties

Conformationally locked tetrasubstituted tolans were synthesized by introducing a tether on the tolan. To demonstrate the utilities of these motifs, a β-hairpin structure (15) was synthesized, and its additional stabilizing effects were evaluated. Moreover, the photophysical properties of cyclic tolans and their β-sheet structure were investigated. The fluorescence quantum yield of cyclic tolan 12 is >1000 times stronger than its congener 1 in CH3CN.