Noteworthy Chemistry

December 10, 2012

This artificial peptide “claw” clutches mercury(II). The amino acid sequence Cys-X-X-Cys (CXXC)—a ubiquitous chelating unit in biological systems, especially metalloproteins—can be integrated into synthetic peptides as metal-binding sites. O. Iranzo and colleagues at the New University of Lisbon (Oeiras, Portugal) and the University of Copenhagen used both cysteine binding residues in the CXXC unit to make tetrapeptide 1. The dPro-Pro β-turn template in 1 forms a Hg(II) complex that is highly stable over a wide pH range. (dPro is D-proline.)

The tetrapeptide was synthesized as Ac-Cys-dPro-Pro-Cys-NH2 (CdPPC). The authors used UV–vis spectroscopy, electrospray-ionization mass spectrometry, and potentiometry to show that CdPPC forms a 1:1 complex with Hg(II) that has a log K (stability constant) of 40.0. Because Hg(II) is strongly thiophilic, its complex with CdPPC is stable from strongly acidic to strongly basic conditions (pH 1.1−10).

The authors synthesized the reference peptide Ac-Cys-Pro-Pro-Cys-NH2 (CPPC) by replacing dPro-Pro with Pro-Pro. CPPC has a significantly lower (3−3.5 orders of magnitude) binding ability toward Hg(II) than CdPPC.

In CdPPC, the dPro-Pro motif induces a predefined secondary structure that mimics binding sites in metalloproteins, which favor Hg(II) coordination geometry. In contrast, the unstructured Pro-Pro motif in CPPC does not form a β-turn template and therefore has weaker binding ability. (Inorg. Chem. 2012, 51, 11339–11348; Xin Su)

Use microneedle technology for sustained transdermal release. M.-C. Chen and colleagues at National Cheng Kung University (Tainan, Taiwan [Province of China]) incorporated biodegradable chitosan in a microneedle patch for sustained, controlled transdermal drug delivery. Using double casting and centrifuging, they deposited a concentrated chitosan hydrogel onto a microneedle mold to prepare 225 microneedle arrays of varying dimensions. Only the first chitosan layer was loaded with model drugs before casting.

Chitosan layering and the compressive forces applied during the manufacturing process yield mechanically robust chitosan microneedle arrays. The authors determined that aspect ratio is a dominant factor in compressive strength and insertion characteristics. A model protein undergoes sustained release for at least 8 days, during which ≈95% of the drug is released. The penetration depth into the dermis layer is ≈300 μm. (Biomacromolecules 2012, 13, Article ASAP; DOI: 10.1021/bm301293d; LaShanda Korley)

Artificial “jellyfish” “breathe” and fluoresce in response to changing pH. In living cells, structural change is often accompanied by function expression. For example, some jellyfish show switchable on–off fluorescence in response to membranes that swell and shrink during the breathing process. Fluorescence is quenched when the jellyfish breathes in; strong fluorescence is emitted when it breathes out. The study of synthetic vesicles as model membranes for mimicking living cells is a growing research area, but all reported cytomimetic processes are limited to morphological transformations. No functions are triggered by the structural variations.

Inspired by the jellyfish, Y. Zhou, X. Zhu, and co-workers at Shanghai Jiao Tong University developed cytomimetic systems with concomitant structural and functional transformations. They used the self-assembly of diblock copolymer 1 in aqueous media to generate “intelligent” polymer vesicles that exhibit pH-induced “breathing” behavior and jellyfish-like on–off switchable fluorescence.

During the “breathing in” process under acidic conditions, vesicle swelling is accompanied by fluorescence quenching as a result of the protonation of 1. Inversely, during the “breathing out” process under alkaline conditions, vesicle shrinking is accompanied by the recovery of strong green fluorescence as a result of the deprotonation process. (Angew. Chem., Int. Ed. 2012, 51, 11633–11637; Ben Zhong Tang)

Here’s a better, safer N-amination of a trisubstituted pyrrole. Z. Shi and co-workers at Bristol-Myers Squibb (New Brunswick and Princeton, NJ) developed a practical synthesis of a p38 kinase inhibitor. In one step, the N-amination of diethyl 3-methyl-1H-pyrrole-2,4-dicarboxylate, O-(2,4-dinitrophenyl)hydroxylamine or chloramine was used originally, but safety and toxicity concerns led to a search for alternative reagents.

O-(p-Nitrobenzoyl)hydroxylamine was a safe alternative, but 2–5% of the p-nitrobenzoylamide of the aminopyrrole formed during the reaction and was difficult to remove by crystallization. The impurity is formed via a 3-hydroxy-oxaziridine intermediate, which suggests that reagents with electron-donating groups on the aromatic ring are less prone to this side reaction.

When the reaction was carried out using O-(p-methoxybenzoyl)hydroxylamine, only 0.3% of the impurity was produced. Alternatively, the p-nitrobenzoylamide impurity can be removed by reducing the nitro group to the aniline with Na2S2O4. The aniline is then extracted into aqueous acid. (Org. Process Res. Dev. 2012, 16, 1618–1625; Will Watson)

Substrates determine reaction condition synergy or inhibition. The activity of SmI2, a one-electron–transfer reducing agent, can be increased or decreased according to reaction conditions. Adding the ligand hexamethylphosphoramide (HMPA) and irradiating with visible light increase the reduction potential of SmI2. C. N. Rao and S. Hoz* at Bar-Ilan University (Ramat-Gan, Israel) report conditions under which HMPA addition and irradiation act synergistically or counterproductively.

The authors chose six aromatic substrates—diphenylacetylene (1), benzonitrile (2), methyl benzoate (3), phenylacetylene (4), naphthalene (5), and 1-chloro-4-ethylbenzene (6)—and subjected them to reduction with SmI2 under these conditions:

  • irradiation without HMPA,
  • irradiation with HMPA, and
  • addition of HMPA in the dark.

The reactions were run in a stopped-flow spectrophotometer using the diode array mode. Reaction progress was monitored by measuring the decrease in optical density of the reaction mixture.

The results showed that a synergistic effect, a nonsynergistic sum of effects, or even an antagonistic effect can occur. Adding HMPA to thermal or photochemical reactions is normally positive because it stabilizes Sm3+ more than the Sm2+ reagent.

The combination of light and HMPA is beneficial only with substrates of sufficiently high electron affinity (13). The reaction of substrates with low electrophilicity (46) is inhibited by adding HMPA because Sm3+ is not present in the vicinity of the radical anion during the rate-determining step. (J. Org. Chem. 2012, 77, 9199–9204; JosÉ C. Barros)

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