Noteworthy Chemistry

November 17, 2014

Triptolide inhibits HIV-1 replication by degrading the Tat protein. The HIV-1 protein Tat is needed for efficient viral gene transcription and replication. HIV-1 inhibitors that target Tat-mediated transcription are the objective of much research, but none of the inhibitors have progressed to clinical trials because of toxicity problems.

Triptolide (1 in the figure) is a diterpenoid triepoxide isolated from the Chinese “thunder god vine” Tripterygium wilfordii (Hook F). It has a wide range of bioactivity, including immunosuppressive and anti-inflammatory properties. Z. Wan and X. Chen* at the Chinese Academy of Sciences (Wuhan) found that nanomolar concentrations of triptolide strongly inhibit HIV-1 replication with no observed toxicity. 

Structure of triptolide

The authors found that triptolide has a dose-dependent inhibitory effect on HIV-1 replication in various cell types. They determined that the compound inhibits the Tat-mediated HIV-1 gene transcription of integrated proviral DNA. Triptolide accomplishes this by selectively targeting and reducing the steady-state Tat levels. Triptolide decreases Tat stability, which is regulated by proteasomes.

When the researchers inhibited proteasomal degradation, they “rescued” Tat protein expression that had been down-regulated by triptolide. This suggests that triptolide enhances Tat proteasomal degradation, which subsequently blocks HIV-1 transcription.

Triptolide’s inhibition mechanism makes it a promising drug against HIV-1 because Tat-mediated viral transcription occurs in latent and chronic infections. The authors believe that triptolide synthesis research should be initiated to provide material for structure–activity relationship studies, determine the functional groups responsible for antiviral activity, and investigate potent triptolide derivatives. (Retrovirology DOI: 10.1186/s12977-014-0088-6; Abigail Druck Shudofsky)

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This continuous hydroxylation is catalyzed by two enzymes. B. Tomaszewksi, A. Schmid, and K. Buehler* at TU Dortmund University (Germany) developed a continuous process that biocatalytically converts 2-hydroxybiphenyl to 3-phenylcatechol. The catalyst is the enzyme 2-hydroxbiphenyl 3-monooxygenase in a decanol–water biphasic medium. The apparatus is a tube-in-tube reactor (TiTR) that delivers oxygen through a semipermeable membrane. The reduced form of cocatalyst nicotinamide adenine dinucleotide (NADH) is regenerated by another enzyme, formate dehydrogenase.

Two TiTR reactors are connected to give the residence time needed for the oxidation. The length of the residence time units is set to 3 m (volume 2.4 mL), which results in a residence time of 3.1 min per residence time unit and 11.5 min in the system at a flow rate of 0.7 mL/min. Oxygen mass transfer is not rate-limiting; rather, the mass transfer of the substrate from decanol to water is the rate-limiting step. (Org. Process Res. Dev. DOI: 10.1021/op5002116; Will Watson)

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Core–shell star polymers are uniform, predictable hosts. Drug-delivery nanocarriers are useful in therapies in which circulation and release times must be carefully controlled. Self-assembled micelles can be used for this purpose, but using linear block copolymers to produce micelles in uniform, predictable sizes, shapes, and compositions can be problematic.

Z. Lin and co-workers at Georgia Tech (Atlanta) produced uniform star-shaped block copolymers that serve as unimolecular micelles or templates for hollow nanoparticles. They synthesized block copolymers with biodegradable cores and photo-cross-linkable shells and controlled the core diameters and shell thicknesses by tuning the molecular weights of the polymer blocks. Varying the ultraviolet light intensity and irradiation time produced various cross-link densities in the shells.

The authors synthesized 21-arm starlike polycaprolactone (PCL) particle cores and functionalized the ends of the star arms with 2-dodecylthiocarbonothioylthio-2-methylpropionic acid. This allowed them to add 4-chloromethylstyrene shell blocks on the ends of the arms, forming polycaprolactone-b-poly(4-chloromethylstyrene), or PCL-b-P(SCl). The chlorine groups on the shell blocks were then replaced with azido groups to produce starlike PCL-b-P(SN3). After the azide groups are cross-linked to form a spherical shell, the core blocks can be degraded and removed by heating the star polymers in dioxane and hydrochloric acid to form hollow particles (see figure). 

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Synthetic strategy for unimolecular polymeric core–shell and hollow nancapsules

Nanoparticles with intact cores can be mixed with guest molecules before the outer shell is cross-linked. Cross-linking the shell blocks entraps the guest molecules, which can be released under controlled conditions. The authors loaded their nanoparticles with dye molecules to test this concept, and they used fluorescence spectroscopy to monitor the release behavior. (Chem. Mater. DOI: 10.1021/cm503108z; Nancy McGuire)

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Ultrasound enhances nanoparticle fluorescence. Fluorescent organic nanoparticles attract attention because of their potential applications in such fields as photonics, optoelectronics, chemosensing, and bioimaging. Researchers, therefore, want to find simple ways to modulate the structure and emission of nanoparticles.

G. Brancato, D. M. Guldi, G. Bottari, and coauthors at Friedrich Alexander University Erlangen-Nŭrnberg (Germany), the Autonomous University of Madrid, IMDEA-Nanociencia (Madrid), and Scuola Normale Superiore (Pisa, Italy) developed an ultrasound-based method for tuning the morphology and fluorescence of molecular rotor nanoparticles.

4-(Diphenylamino)phthalonitrile (1 in the figure) is a structurally simple molecular rotor that does not emit light in methanol solution; it has a quantum yield of 0.0021 and a lifetime of 0.56 ns. When molecules of 1 aggregate in a 13:87 methanol–water mixture, the emission and lifetime increase by >20-fold. 

Structure of 4-(diphenylamino)phthalonitrile

When the amorphous spherical nanoparticles of 1 are ultrasonicated for 1 min, they transform into stable rhomboidal nanocrystals. With the structural change, the light emission intensifies by another threefold. This work provides an example of ultrasound-induced tuning of the morphology and light emission of organic nanoparticles. (Chem. Commun. DOI: 10.1039/C4CC05531D; Ben Zhong Tang)

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Improve macrocyclic ring closure with modified click reactions. Copper-catalyzed azide–alkyne cycloaddition (CuAAC), the most notable example of a click reaction, is a widely used ring-closure method in macrocycle synthesis, especially in medicinal chemistry. It has several drawbacks, however, including slow reaction rates, high catalyst loadings, and low yields, that limit its efficacy.

A.-C. Bédard and S. K. Collins* at the University of Montreal improved the performance of this macrocyclization method by replacing the terminal hydrogen atom of azide–alkyne substrates with an iodine atom (the CuAiAC reaction). They examined phase-separation reaction conditions, in which poly(ethylene glycol) (PEG) cosolvents minimize dilution effects in the synthesis. They found that azide–iodoalkynes (e.g., 1 in the figure), at 30-mM concentration, cyclize into iodotriazole macrocycles such as 2 in 97% yield in the presence of 5 mol% copper(I) iodide and 2 equiv triethylamine in a 2:1 PEG400–MeOH solvent mixture. 

Cyclization reaction of iodoalkyne azides

When the researchers increased the concentration of 1 to 100 mM and then to 300mM, the ring closure yield decreased only to 76 and 58%, respectively. They also demonstrated that the modified reaction is compatible with a variety of substrates, including peptidic macrocyclic precursors.

This technique can be readily scaled up by using a continuous-flow setup and high substrate concentrations without decreasing the yield. The iodo-substituted triazole group also allows the-ring-closed product to be functionalized via cross-coupling reactions. (Org. Lett. DOI: 10.1021/ol502415a; Xin Su)

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Derivatize methyl oleate to control fluid viscosity. Fatty acid methyl esters (FAMEs) are important biodegradable materials that are used in hydraulic fluids, surfactants, and adhesives and as chemical building blocks. But two key characteristics of FAMEs need to be improved: their cold-flow properties and oxidative stability.

T. Maschmeyer and co-workers at the University of Sydney (Australia) chemically modified the FAME methyl oleate to modulate its viscosity. They prepared a series of methyl 9-alkoxy (or carboalkoxy)-10-hydroxy- and 10-alkoxy (or carboalkoxy)-9-hydroxystearates (3 and 4) by epoxidizing methyl oleate (1) and ring-opening the epoxide (2) (see figure). 

Preparation of methyl 9(10)-alkoxy-10(9)-hydroxystearates

The authors also transesterified the terminal carboxyl groups of some of these compounds. They found that cyclic hydrocarbon groups in the structure of the oils provided viscous flow activation energies that ranged from 28 to 41 kJ/mol.

Capping the hydroxyl group with ethers rather than esters in the side chain or removing the hydroxyl group gave the most suitable candidates for industrial lubricants. Transesterification of the methyl groups improves the properties even more. The new compounds, however, do not have improved properties for use as biodiesel fuels. (New J. Chem. DOI: 10.1039/C4NJ01453G; José C. Barros)

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