Noteworthy Chemistry

September 5, 2011

Visualize tumor cells with folate receptor–targeting nanoprobes. One challenge to developing and implementing two-photon fluorescence microscopy for molecular bioimaging is the lack of biocompatible probes with large two-photon absorption (2PA) cross-sections, high emission efficiency, and strong photobleaching resistance under physiological conditions. Organic molecules with large 2PA coefficients are synthetically more accessible in hydrophobic forms; their emission efficiency is often dramatically reduced in aqueous media by aggregation-caused quenching (ACQ).

K. D. Belfield and coauthors at the University of Central Florida (Orlando), Sanford–Burnham Medical Research Institute at Lake Nona (Orlando), Anhui Polytechnic University (Wuhu, China), and the Institute of Physics (Kiev, Ukraine) designed and synthesized a highly 2PA-active pyran derivative (1) that has a new type of aggregation-enhanced emission. Aggregates of 1 encapsulated in silica nanoparticles function as folate receptor (FR)–targeting nanoprobes for two-photon fluorescence bioimaging that overcome the ACQ problem associated with high chromophore loading in conventional fluorophore systems.

The researchers prepared silica nanoparticles to encapsulate the aggregates of 1 and functionalized the nanoparticle surfaces with folic acid derivatives. Compared with solutions of 1, the nanoparticles exhibit about twofold brighter light emission, threefold higher 2PA activity, and fourfold stronger photobleaching resistance.

The biocompatible nanoparticles are selectively taken up by FR-overexpressing HeLa cells and are efficient probes for in vivo bioimaging when they are administered intravenously into mice that have HeLa tumors. The nanoparticles selectively accumulate in the tumors, most likely by an FA-mediated active targeting mechanism. They penetrate deep into the tumor parenchyma, as shown by cellular-level 2PA imaging of whole-tumor mounts. (Bioconjugate Chem. 2011, 22, 1438–1450; Ben Zhong Tang)

A radioactive fluorine–labeled imidazobenzothiazole derivative provides high-contrast PET imaging for β-amyloid plaques. A primary marker for Alzheimer’s disease (AD) is the accumulation of senile plaques formed by β-amyloid peptides (Aβ). One of the most useful techniques for noninvasive AD imaging is based on 18F-labeled positron emission tomography (PET) tracers. The current goals for improving this method include higher binding efficiency of the tracers to Aβ-plaques to detect less-extensive amyloid pathology in patients in early clinical stages.

New 18F-labeled tracers should have improved brain uptake and clearance kinetics, high in vivo metabolic stability, and most importantly, high binding affinity to Aβ-plaques. B. H. Yousefi, G. Henriksen, and co-workers at the Technical University of Munich (Munich and Garching, Germany) report the use of 18F-labeled imidazo[2,1-b]benzothiazole derivative 1. They describe a six-step radiosynthesis of 1 in which the 18F radionuclide is incorporated in the final step; TsO is p-toluenesulfonate. The sequence outlined in the figure produces 1 with high (>99%) chemical and radiochemical purity.

The imidazobenzothiazole scaffold in 1 is suitably lipophilic for in vivo imaging of brain targets. In a series of studies, the authors evaluated the binding affinity of 1, including calculating or measuring inhibition constants, brain uptake kinetics, lipophilicity, metabolic stability, and clearance properties. They imaged Aβ in vivo in a double transgenic APP/PS1 mouse model.

Based on the PET and computed tomography scans and ex vivo data from this mouse model, they showed specific binding of 1 to Aβ plaques in the hippocampal and cortical regions of the brain. The test animals were euthanized 45 min after being injected with 1, and autoradiography data from their brain sections verified the cortical uptake of 1 shown in the PET studies. These data indicate that the observed uptake of 1 represents true binding to cortical Aβ-plaques.

Results of the evaluation demonstrate excellent brain uptake and clearance profiles. The accumulated data from this study justify further evaluation of 1 for detecting amyloid plaques in the living brain at an early stage of AD, when the condition may be more responsive to medical intervention. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml200123w; W. Jerry Patterson)

Synthesize an API in six steps without isolating intermediates. M. S. Anson, J. P. Graham*, and A .J. Roberts at GlaxoSmithKline Research and Development (Stevenage, UK) report a “fully telescoped” synthesis of a selective sphingosine-1-phosphate receptor subtype 1 agonist. The first step is the nucleophilic displacement of the 4-fluoro group in 4-fluoro-3-trifluoromethylbenzoic acid with 1-octanol. The octyloxy side chain is present in the all subsequent compounds; it is almost certainly responsible for the lack of crystalline intermediates, but the final active pharmaceutical ingredient (API) can be isolated as a dihydrochloride or hemifumarate salt.

Because of the inability to obtain crystalline intermediates, the researchers focused on reagent stoichiometry, workup of each step, and, in the first step, a foaming problem. The nucleophilic displacement was originally carried out with 2.5 equiv of KO-t-Bu in refluxing THF with significant foaming. Running the reaction at 3–5 °C below reflux, however, prevents foaming.

Adding some water, followed by solvent swap to water, gives a mobile slurry of the carboxylate salt that is extracted into MeO-t-Bu; all byproducts remain in the discarded aqueous layer. The salt is extracted back into water; and after acidification, the free octyloxy acid is extracted into 2-methyltetrahydrofuran, which is the solvent for the next synthesis stage. (Org. Process Res. Dev. 2011, 15, 649–659; Will Watson)

Sculpt nanoscale wires and tubes from fluorescent salts. Ionic liquids are fused salts that have melting points <100 °C and typically comprise bulky, asymmetric semiorganic cations and anions. Groups of uniform materials based on organic salts (GUMBOS) are cousins of ionic liquids that are not fluid near ambient temperature but have melting points up to 250 °C. They, like ionic liquids, have physicochemical properties that can be modified by changing the structures of the component ions.

I. M. Warner and coauthors at Louisiana State University (Baton Rouge), Spring Hill College (Mobile, AL), and Horiba Jobin Yvon (Edison, NJ) used a simple one-step anion-exchange reaction to develop a novel fluorescent GUMBOS based on pairing rhodamine 6G with tetraphenylborate (1). In addition to the fluorescent properties introduced by the cation, the bulky anion makes the salt highly hydrophobic.

One-dimensional (1-D) nanomaterials—including nanowires, nanotubes, and nanoarrays—can be prepared from this salt by using anodic alumina (AAO) as a hard sacrificial template. After the template is dissolved in acid, solutions of 1 are dropcast onto the AAO to yield nanotubes at lower concentrations and nanowires at higher concentrations. Likewise, nanoarrays can be prepared by immobilizing the templates onto an appropriate surface before removing the template.

These 1-D fluorescent nanostructures from organic salts may be useful in optics and photonics, for example, in waveguiding and lasing. With this templating method, nanomaterials with other properties such as chirality, paramagnetism, and electroluminescence can be developed for diverse sensing applications. (Chem. Commun. 2011, 47, 8916–8918; Gary A. Baker)

N-Heterocyclic carbene catalysis promotes lactone formation. As part of their research into enal homoenolate intermediates for cascade reactions, X. Fang, X. Chen, and Y. R. Chi* at Nanyang Technological University (Singapore) recently described the use of N-heterocyclic carbene (NHC) catalysis for directly generating NHC-bound enolates from enals (Fang, X., et al. Angew. Chem., Int. Ed. 2011, 50, 1910–1913). They now report an elaboration of this work in which a chalcone with an electron-withdrawing group in its α-position (1) reacts with enals (e.g., 2) in the presence of chiral NHC catalyst 3; Mes is mesityl. Catalyst 3 is converted in situ to the corresponding carbene, which selectively activates 2 to form an enolate equivalent that undergoes an enantioselective Diels–Alder cyclization with 1 and produces functionalized lactones such as 4.

The presence of strong bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is essential for optimum reaction efficiency. The authors stress that no homoenolate pathway products are produced—a significant difference from other reports in which chalcones are used as substrates in NHC catalysis.

In the case of β-arylenal reactants, the Diels–Alder products are generated in essentially optically pure form with high yields. With β-alkylenals, however, a bulky imidazolium-based NHC catalyst is needed to obtain even modest yields of the Diels–Alder products. (Org. Lett. 2011, 13, 4708–4711; W. Jerry Patterson)

Use sunlight to deprotect alcohols. Photolabile protecting groups (PPGs) are useful structures in organic chemistry, biochemistry, photolithography, and materials science when light is used as a traceless reagent for removing them. Dimethylaminotrityl (DMATr) groups are among the most efficient PPGs for protecting alcohols (see figure).

L. Zhou, H. Yang, and P. Wang* at the University of Alabama at Birmingham studied PPGs with trityl substituents such as DMATr and 4-methoxytrityl to establish how structure affects reactivity. Using the m-dimethylamino-substituted trityl protecting group as a baseline, they screened the effects of other electron-releasing groups (OH, OAc, OMe, and O-tert-butyldimethylsilyl) on trityl and found no noticeable advantages over DMATr. PPGs with two dimethylamino-substituted aromatic rings likewise did not result in better yields.

The authors replaced the laboratory UV-light source with sunlight to decompose DMATr-protected alcohols. With H2O–MeCN as the solvent, mannoside 1 is deprotected at 20–30 °C after 4.5 h with yields >80%. This strategy can be used in large-scale applications because it does not require a special photochemical apparatus. (J. Org. Chem. 2011, 76, 5873–5881; JosÉ C. Barros)

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