Noteworthy Chemistry

December 17, 2012

A luminogen without a conventional chromophore emits efficiently in the aggregated state. Typical organic luminophores are aromatic molecules with extended π-electron conjugation. There are few examples of luminogens in nonconjugated molecules. A research team led by R. Shunmugam at the Indian Institute of Science Education and Research (Kolkata) synthesized a norbornenyl phosphonate (1) that emits intense blue light when photoexcited

Theoretical calculations suggest that differences between the positions of the HOMO and LUMO wave functions are responsible for the unusual luminescence. The strong fluorescence of 1 can be used to detect the biologically important target Fe(III) rapidly in aqueous media and biological environments.

As in other luminogens that do not contain traditional chromophores, 1 is rich in heteroatoms with nonbinding lone pairs. Its luminescence is boosted dramatically when its molecules are aggregated. This finding suggests the existence of an unconventional “chromophore” that consists of aggregating clusters of the heteroatom units. Electronic interactions in such lone-pair clusters may make 1 emissive in the aggregated state. (Nanoscale 2012, 4, 6962–6966; Ben Zhong Tang)

Levulinate may replace GHB as an illicit drug. H. Brunengraber and co-workers at Case Western Reserve University (Cleveland) describe the metabolism of levulinate (4-ketopentanoate) to diketone–coenzyme A esters. The diketone metabolites’ ability to react with lysines to give pyrrolated proteins or cyclize to make cyclopentene derivatives suggests a new mechanism for levulinate toxicity.

The authors point out that

  • calcium levulinate is freely available as a calcium supplement; and
  • in vivo, levulinate is reduced to 4-hydroxypentanoate, which has pharmacologic effects similar to 4-hydroxybutyrate (GHB, a “date-rape” drug).

The conversion is markedly increased in the presence of EtOH. Now that GHB is a controlled substance, there is concern that people will take calcium levulinate and alcohol to obtain the same effects. Because 4-hydroxypentanoate has a weaker drug effect and is more toxic than GHB, its biological and toxicological mechanisms are important. (Chem. Res. Toxicol. 2013, 26, Article ASAP DOI: tx3003643; Carol A. Rouzer)

[Carol A. Rouzer is the managing editor of Chemical Research in Toxicology.—Ed.]

Here’s an easy, trouble-free synthesis of benzothiazoles. 2-Substituted benzothiazoles are an important class of compounds because of their biological activity and potential for creating new materials. Current synthetic methods for 2-substituted benzothiazoles, however, often have prolonged reaction times, harsh reaction conditions, and low functional-group tolerance. S. Meghdadi* and M. Amirnasr* at Isfahan University of Technology (Iran) and P. C. Ford at the University of California, Santa Barbara, simplified the synthesis by using the simple ionic liquid Bu4NBr as the solvent and P(OEt)3 as the catalyst.

The condensation reaction between 2-aminothiophenol (1) and aryl or heteroaryl carboxylic acids to yield the corresponding 2-substituted benzothiazoles is well known. The authors’ method uses relatively low temperatures (≈120 °C) and short reaction times (15–60 min). In the workup, Bu4NBr and P(OEt)3 are removed with MeOH, avoiding the need for chromatography.

The reaction conditions tolerate carboxylic acid substrates, including a variety of substituted benzoic acids, naphthoic acids, and N-heteroaryl carboxylic acids. The yields in all cases are >60%, much higher than in traditional methods. In the authors’ proposed mechanism, 1 and intermediate 2 form a thioester (3), which dehydrates and cyclizes to yield the benzothiazole (4). (Tetrahedron Lett. 2012, 53, 6950–6953; Xin Su)

Reduce a nitro group independently of four other functionalities. W. P. Gallagher and co-workers at Bristol-Meyers Squibb (New Brunswick, NJ) developed a selective reduction of the nitro group in 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine. Most of the reducing agents they tried over-reduced the imine—in some cases cleaving the subsequent benzhydryl group—or under-reduced it, leaving the corresponding hydroxylamine as an impurity.

The hydroxylamine could not be removed by crystallization, so it was necessary to minimize its formation. The authors developed a scalable method by using (NH4)2S as the reducing agent. The success of the reaction, however, depended greatly on the source of the (NH4)2S and the scale of the reaction. Isolated yields varied from 53% to 80%.

Hydrogenation over sponge nickel at 25 °C and 25 psig hydrogen in 2-methyltetrahydrofuran solvent gave an 88% yield on a 22-kg scale. The activity of the sponge nickel was attenuated by washing with AcOH, H2O, and finally MeOH. (Org. Process Res. Dev. 2012, 16, 1665–1668; Will Watson)

Take an amphiphilic route to encapsulating a hydrophobic drug. N. Bailly, M. Thomas, and B. Klumperman* at Stellenbosch University (Matieland, South Africa) investigated vesicles formed from amphiphilic block copolymers with varying the hydrophobic block lengths as potential carriers for hydrophobic drugs such as clofazimine. The BCPs consisted of hydrophilic poly(N-vinylpyrrolidone) (PVP) and hydrophobic poly(vinyl acetate) (PVAc) They used dialysis to promote the self-assembly of the block copolymer (BCP) followed by drug encapsulation.

The authors found that drug loading minimally affects vesicle size, and it does not alter BCP assembly up to 1:4 w/w loads. Loading efficiency and capacity increase with increased molecular weight of the PVAc block. The hydrophilic PVP layer stabilizes the BCP carriers and their clofazimine-loaded analogues for ≈15 h in PBS buffer with and without added serum under physiological conditions. Incorporating clofazimine in the biocompatible PVP-b-PVAc vesicles causes greater cytotoxicity in a breast-cancer cell line than treatment with unencapsulated clofazimine. (Biomacromolecules 2012, 13, 4109–4117; LaShanda Korley)

Crown ether host-rotaxanes kill tumor cells via programmed cell self-destruction. Synthetic ionophores, such as crown ethers, selectively bind cations based on their size and charge and have some antitumor properties. In 2010, D. B. Smithrud and coauthors at the University of Cincinnati and the Cincinnati Veterans Affairs Medical Center reported crown ether host-rotaxanes (CEHRs) that can transport various cations (Wang, X; Zhu, J.; Smithrud, D. B. J. Org. Chem. 2010, 75, 3358–3370). They propose using these molecules to introduce Mg2+ or Ca2+ into tumor cells to provoke apoptosis (programmed cell death).

The authors investigated the cytotoxicities of tert-butoxycarbonyl (Boc)–CEHR (1) and arginine (Arg)–CEHR (2) on SKOV-3 ovarian cancer cells by adding different concentrations of Mg2+ or Ca2+ to the cell medium. They discovered that increasing the Ca2+ concentration consistently increases the toxicities of both CEHRs. The results with Mg2+, however, were inconsistent: Boc-CEHR was much more toxic than Arg-CEHR. Evaluation of the results confirmed that CEHR cytotoxicity comes from increased intracellular concentrations of the cations to induce apoptosis, not from necrosis (death by cell damage).

These results may lead to treating tumor cells by inducing apoptosis. Further research is under way to build CEHRs that bind more tightly to Ca2+ to selectively target tumor cells. (ACS Med. Chem. Lett. 2012, 3, Article ASAP DOI: 10.1021/ml3003204; Chaya Pooput)

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