Organic & Biomolecular Chemistry (v.15, #28)
Front cover (5857-5857).
Inside front cover (5858-5858).
Contents list (5859-5866).
Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials by Charlotte J. C. Edwards-Gayle; Ian W. Hamley (5867-5876).
Molecular self-assembly is a multi-disciplinary field of research, with potential chemical and biological applications. One of the main driving forces of self-assembly is molecular amphiphilicity, which can drive formation of complex and stable nanostructures. Self-assembling peptide and peptide conjugates have attracted great attention due to their biocompatibility, biodegradability and biofunctionality. Understanding assembly enables the better design of peptide amphiphiles which may form useful and functional nanostructures. This review covers self-assembly of amphiphilic peptides and peptide mimetic materials, as well as their potential applications.
Is more better? A comparison of tri- and tetrapeptidic catalysts by Tobias Schnitzer; Markus Wiesner; Philipp Krattiger; Jefferson D. Revell; Helma Wennemers (5877-5881).
From an enzymatic perspective, there is a general notion that the bigger and more complex a catalytically active peptide is the more enzyme-like and the better it should become. But is this really true? We have tackled this question firstly by screening split-and-mix-libraries of tri- and tetrapeptides for members that catalyze aldol reactions. Then, the catalytic performance of all possible diastereoisomers of related tri- and tetrapeptidic catalysts of the type H-Pro-Pro-Glu/Asp-NH2 and H-Pro-Pro-Glu/Asp-Pro-NH2 in aldol and conjugate addition reactions was compared.
Enhancing a long-range salt bridge with intermediate aromatic and nonpolar amino acids by Mason S. Smith; Wendy M. Billings; Frank G. Whitby; McKenzie B. Miller; Joshua L. Price (5882-5886).
The interaction of a positively charged amino acid residue with a negatively charged residue (i.e. a salt bridge) can contribute substantially to protein conformational stability, especially when two ionic groups are in close proximity. At longer distances, this stabilizing effect tends to drop off precipitously. However, several lines of evidence suggest that salt-bridge interaction could persist at longer distances if an aromatic amino acid residue were positioned between the anion and cation. Here we explore this possibility in the context of a peptide in which a Lys residue occupies the i + 8 position relative to an i-position Glu on the solvent-exposed surface of a helix-bundle homotrimer. Variable temperature circular dichroism (CD) experiments indicate that an i + 4-position Trp enables a favorable long-range interaction between Glu and the i + 8 Lys. A substantial portion of this effect relies on the presence of a hydrogen-bond donor on the arene; however, non-polar arenes, a cyclic hydrocarbon, and an acyclic Leu side-chain can also enhance the long-range salt bridge, possibly by excluding water and ions from the space between Glu and Lys.
Synthesis of 2,3′-spirobi[indolin]-2-ones enabled by a tandem nucleophilic benzylation/C(sp2)–N cross-coupling reaction sequence by Baodong Cui; Jing Shan; Changlun Yuan; Wenyong Han; Nanwei Wan; Yongzheng Chen (5887-5892).
An efficient complementary strategy for the construction of spiro[pyrrolidin-3,2′-oxindole] derivatives has been described. With the sequential nucleophilic benzylation and copper-catalyzed intramolecular C(sp2)–N cross-coupling reaction of 3-aminooxindoles with 2-bromobenzyl bromides, a wide range of 2,3′-spirobi[indolin]-2-ones were smoothly obtained in moderate to good yields. A plausible catalytic cycle for this tandem reaction process was proposed based on the control experiments. This study represents a new perspective for the synthesis of structurally diverse spirocyclic oxindoles by employing 3-aminooxindole substrates.
Collagen mimetic peptide discs promote assembly of a broad range of natural protein fibers through hydrophobic interactions by Kenneth McGuinness; Vikas Nanda (5893-5898).
Collagen mimetic peptides that alone formed two-dimensional nanoscale discs driven by hydrophobic interactions were shown in electron microscopy studies to also co-assemble with natural fibrous proteins to produce discs-on-a-string (DoS) nanostructures. In most cases, peptide discs also facilitated bundling of the protein fibers. This provides insight into how synthetic and natural proteins may be combined to develop multicomponent, multi-dimensional architectures at the nanoscale.
Dual visible-light photoredox and palladium(ii) catalysis for dehydrogenative C2-acylation of indoles at room temperature by Manash Kumar Manna; Gurupada Bairy; Ranjan Jana (5899-5903).
A highly regioselective direct C2-acylation of N-pyrimidine protected indoles with aldehydes is reported at room temperature through the merger of visible light photoredox and palladium(ii) catalysis. Late-stage acylation of tryptophan, selective mono-acylation of carbazole and the syntheses of tubulin inhibitors D-64131 and D-68144 are also demonstrated.
Copper-mediated trifluoroacetylation of indoles with ethyl trifluoropyruvate by Guobing Yan; Xihan Cao; Wanbin Zheng; Qiumin Ke; Jieyu Zhang; Dayun Huang (5904-5907).
Direct trifluoroacetylation of indoles with ethyl trifluoropyruvate as a trifluoroacetylating reagent has been developed. This novel protocol provides an attractive route for the preparation of 3-trifluoroacetylindole derivatives, due to its operational simplicity and practicability as well as mild reaction conditions.
Formal total synthesis of selaginpulvilin D by Bhavani Shankar Chinta; Beeraiah Baire (5908-5911).
An efficient and mild synthetic strategy for the total synthesis of selaginpulvilin D has been reported. A highly chemoselective enyne–alkyne dehydro Diels–Alder reaction has been employed for the construction of the tricyclic fluorene framework present in the natural product selaginpulvilin D. An improved overall yield (10.5%) has been achieved for selaginpulvilin D, starting from commercially available m-anisaldehyde in 9 linear, operationally simple synthetic transformations.
Synthesis and biological evaluation of N-arylated-lactam-type iminosugars as potential immunosuppressive agents by Hai-Qian Liu; Cheng-Cheng Song; You-Hong Niu; Tao Li; Qin Li; Xin-Shan Ye (5912-5919).
Since the immunosuppressive agents currently used in clinics have significant side effects, it is very important to search for new effective and safe immunosuppressants. Iminosugars as a new class of immunosuppressants are less explored. In this report, 24 new N-arylated iminosugar derivatives, including d-talo and d-galacto epimers, were designed and synthesized, and their immunosuppressive effects were evaluated by MTT assay. The experimental data demonstrated that compound 20 showed the strongest inhibition effect (IC50 = 6.94 μM). Further studies revealed that the inhibitory effects on splenocyte proliferation may come from the suppression of both IFN-γ and IL-4 cytokines. The preliminary structure–activity relationship (SAR) analysis suggested that N-arylated d-galacto-type iminosugars showed better inhibitory activities than d-talo-type analogues. The SAR analysis also showed that the inhibition effect of iminosugars can be improved by decreasing the polarity or increasing the hydrophobicity. These results may be beneficial to the discovery of new iminosugar derivatives as immunosuppressive agents.
Governing effects in the mechanism of the gold-catalyzed cycloisomerization of allenic hydroxylamine derivatives by Sofia Kiriakidi; Olalla Nieto Faza; Antonios Kolocouris; Carlos Silva López (5920-5926).
The formation of chiral heterocycles via cycloisomerization reactions of allene derivatives has gained relevance due to their associated efficiency and atom-economy. The only drawback that keeps these reactions away from being routine synthetic strategies is the control in the regioselectivity (most often 5-endo vs. 6-endo). In this work, we computationally explore the experimental chemistry reported by Krause using N-hydroxy-α-aminoallenes and hydroxylamine ethers as substrates and provide a rationale for the different reactivity observed. The drastic effects observed experimentally when changing the nature of the gold catalyst have also been studied mechanistically. These results are expected to help in the design of improved regioselective protocols for the formation of medium sized chiral heterocycles from allene substrates.
Catching the chloride: searching for non-Hofmeister selectivity behavior in systematically varied polyamide macrocyclic receptors by Kajetan Dabrowa; Filip Ulatowski; Dawid Lichosyt; Janusz Jurczak (5927-5943).
The binding selectivity of structurally simple anion receptors is governed by the Hofmeister series (SO42− > HPO42− > carboxylates ∼ H2PO4− > HCO3− > Cl−), and exceptions to this rule are rare and require utilization of structurally sophisticated receptors. In this paper we examined a set of 48 structurally diverse anion receptors, barely one fourth of which exhibit selectivity for chloride over more basic dihydrogen phosphate (H2PO4−) or carboxylates (MeCO2− and PhCO2−). Searching for regularities in the properties of these mainly macrocyclic-derived receptors across quite systematic changes in structure, combined with analysis of multiple crystal structures, allowed us to identify the crucial structural features that are likely required for the occurrence of the phenomenon of selective chloride binding. Examination of a subset of other ‘case study’ receptors reported in the literature as being particularly chloride-selective served as a confirmation of our hypotheses. As such, our findings are valid for all artificial receptors with exceptional selectivity for chloride, as well as for natural chloride channel proteins (ClC).
Oxidative coupling of Michael acceptors with aryl nucleophiles produced through rhodium-catalyzed C–C bond activation by Caroline E. Gregerson; Kathryn N. Trentadue; Erik J. T. Phipps; Janelle K. Kirsch; Katherine M. Reed; Gabriella D. Dyke; Jacob H. Jansen; Christian B. Otteman; Jessica L. Stachowski; Jeffrey B. Johnson (5944-5948).
Utilizing rhodium catalysis, aryl nucleophiles generated via carbon–carbon single bond activation successfully undergo oxidative coupling with Michael acceptors. The reaction scope encompasses a broad range of nucleophiles generated from quinolinyl ketones as well as a series of electron deficient terminal alkenes, illustrating the broad potential of intersecting carbon–carbon bond activation with synthetically useful coupling methodologies. The demonstrated oxidative coupling produces a range of cinnamyl derivatives, several of which are challenging to prepare via conventional routes.
Fluorine-containing bistolanes as light-emitting liquid crystalline molecules by Shigeyuki Yamada; Kazuya Miyano; Tsutomu Konno; Tomohiro Agou; Toshio Kubota; Takuya Hosokai (5949-5958).
We synthesised a series of dissymmetric bistolane derivatives and evaluated their liquid-crystalline (LC) and photoluminescence properties in detail. In measuring LC behaviours, rational structural design based on the dissymmetric molecular structure and electron-density distribution facilitated the production of the LC phase with a wide temperature range (up to 97 °C). In addition, dissymmetric bistolane derivatives were shown to strongly emit blue-photoluminescence in dilute solution and in crystalline states. It was found that dissymmetric bistolanes possess emissive features in even the LC phase and photoluminescence behaviours such as emission intensity and colour were sensitively switched depending on the molecular aggregate structure caused by applying a thermal stimulus.
A chromogenic and ratiometric fluorogenic probe for rapid detection of a nerve agent simulant DCP based on a hybrid hydroxynaphthalene–hemicyanine dye by Syed Samim Ali; Ankita Gangopadhyay; Kalipada Maiti; Sanchita Mondal; Ajoy Kumar Pramanik; Uday Narayan Guria; Md. Raihan Uddin; Sukhendu Mandal; Debasish Mandal; Ajit Kumar Mahapatra (5959-5967).
A new cyanine dye (CYD) based on hybrid hydroxynaphthalene–hemicyanine has been synthesized and characterized. The chromogenic and ratiometric fluorogenic probe (CYD) enables a fast and highly sensitive response to an OP nerve agent mimic diethyl chlorophosphate (DCP) through tandem phosphorylation and intramolecular cyclization reaction within 1 min and with the detection limit as low as 18.86 nM. To our knowledge this is the first report of a hydroxyl assisted bathochromic shift in a selective chemodosimeter for DCP exhibiting a ratiometric response. TDDFT calculations were performed in order to demonstrate the electronic properties of the probe and the cyclized product. Moreover, the utility of the probe CYD for the detection of DCP in live cells, in the gas phase and in a spiked soil sample has also been demonstrated.
Selective turn-on fluorescence sensing of sulfate in aqueous–organic mixtures by an uncharged bis(diamidocarbazole) receptor by Krzysztof M. Bąk; Krystyna Masłowska; Michał J. Chmielewski (5968-5975).
A linear, uncharged, hydrogen bonding receptor A with two carbazole-based binding domains was synthesised and evaluated for its anion binding properties in DMSO/H2O mixtures. 1H NMR titrations revealed that, in DMSO/H2O 0.5%, A forms both 1 : 1 and 1 : 2 complexes with SO42−, H2PO4−, PhCOO− and Cl−. In 1 : 1 complexes the receptor encloses the tetrahedral anions tightly, forming a helical structure, while Cl− binds with a single carbazole unit only. In the presence of 10% of water the 1 : 2 complexes with SO42− and PhCOO− disappear, and the respective 1 : 1 binding constants decrease sufficiently to be quantified by UV-Vis titration. In this highly competitive medium, A binds sulfate with K1:1 = 105.47 M−1, i.e., it binds approx. 30, 360 and >1000 times more strongly than H2PO4−, PhCOO− and Cl−, respectively. Furthermore, the association with sulfate is over 50 times stronger than that for a model diamidocarbazole 1 under identical conditions, suggesting a very strong chelating effect due to the diglycoyl linker. Increasing the amount of water to 25% (the solubility limit of A) lowers the 1 : 1 binding constant with SO42− to 103.73 M−1. Receptor A was shown to act as a selective turn-on fluorescent sensor for sulfate, able to sense sulfate in sulfate-rich mineral water.
[18F]Fluoroalkyl azides for rapid radiolabeling and (Re)investigation of their potential towards in vivo click chemistry by Christoph Denk; Martin Wilkovitsch; Philipp Skrinjar; Dennis Svatunek; Severin Mairinger; Claudia Kuntner; Thomas Filip; Johannes Fröhlich; Thomas Wanek; Hannes Mikula (5976-5982).
In recent years, radiofluorinated alkyl azides have been reported for click radiolabeling and pretargeted PET imaging, but only little is known about the biodistribution and metabolism of these compounds. In this work, we present a significantly improved procedure for the synthesis of [18F]fluoroethyl azide and reinvestigated this radiolabeled probe in detail showing poor stability and very restricted suitability for in vivo application. Therefore, modified low-molecular-weight [18F]fluoroalkyl azides were developed. Propargyl-tagged endomorphin-1 (as model compound) was successfully radiolabeled in high yield and short reaction time making these probes useful and efficient bioorthogonal tools for rapid radiolabeling. Biodistribution, pharmacokinetics and in vivo stability were studied by preclinical PET/MR scanning and metabolite analysis. The results of this study revealed only limited applicability of [18F]fluoroalkyl azides for in vivo application.
Intermolecular sulfenoamination of alkenes with sulfonamides and N-sulfanylsuccinimides to access β-sulfonylamino sulfides and dihydrobenzothiazines by Tao Liu; Jun Tian; Wen-Chao Gao; Hong-Hong Chang; Qiang Liu; Xing Li; Wen-Long Wei (5983-5992).
An acid-catalyzed intermolecular sulfenoamination reaction of alkenes is developed with sulfonamides as the nitrogen source and N-sulfanylsuccinimides as the sulfur source. This methodology provides a straightforward and general way to synthesize various β-sulfonylamino sulfides with high regio- and diastereoselectivity. The developed method was coupled with intramolecular C–N coupling in a one-pot procedure to afford a series of dihydrobenzothiazine derivatives, a kind of important heterocycle used as biologically active compounds in medicinal chemistry.
α-Halo carbonyls enable meta selective primary, secondary and tertiary C–H alkylations by ruthenium catalysis by Andrew J. Paterson; Callum J. Heron; Claire L. McMullin; Mary F. Mahon; Neil J. Press; Christopher G. Frost (5993-6000).
A catalytic meta selective C–H alkylation of arenes is described using a wide range of α-halo carbonyls as coupling partners. Previously unreported primary alkylations with high meta selectivity have been enabled by this methodology whereas using straight chain alkyl halides affords ortho substituted products. Mechanistic analysis reveals an activation pathway whereby cyclometalation with a ruthenium(ii) complex activates the substrate molecule and is responsible for the meta selectivity observed. A distinct second activation of the coupling partner allows site selective reaction between both components.
Design, synthesis, and biological activity of second-generation synthetic oleanane triterpenoids by Liangfeng Fu; Qi-xian Lin; Evans O. Onyango; Karen T. Liby; Michael B. Sporn; Gordon W. Gribble (6001-6005).
We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via“abnormal Beckmann” rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.
Diphenylacrylonitrile-connected BODIPY dyes: fluorescence enhancement based on dark and AIE resonance energy transfer by Liangbin Lin; Xiaoru Lin; Hongyu Guo; Fafu Yang (6006-6013).
This study focuses on the construction of novel diphenylacrylonitrile-connected BODIPY dyes with high fluorescence in both solution and an aggregated state by combining DRET and FRET processes in a single donor–acceptor system. The first BODIPY derivatives with one, two, or three AIE-active diphenylacrylonitrile groups were designed and synthesized in moderate yields. Strong fluorescence emissions were observed in the THF solution under excitation at the absorption wavelength of non-emissive diphenylacrylonitrile chromophores, implying the existence of the DRET process between the dark diphenylacrylonitrile donor and the emissive BODIPY acceptor. In the THF/H2O solution, the fluorescence intensity of the novel BODIPY derivatives gradually increased under excitation at the absorption wavelength of diphenylacrylonitrile chromophores, suggesting a FRET process between diphenylacrylonitrile and BODIPY moieties. A greater number of diphenylacrylonitrile units led to higher energy-transfer efficiencies. The pseudo-Stokes shift for both DRET and FRET processes was as large as 190 nm.
Visible-light mediated directed perfluoroalkylation of hydrazones by Heng Ji; Hui-qiong Ni; Peng Zhi; Zi-wei Xi; Wei Wang; Jian-jun Shi; Yong-miao Shen (6014-6023).
Perfluoroalkylation of N-alkylhydrazones has been achieved via visible light mediated photoredox reactions between the hydrazone and perfluoroalkyl iodide (RfI). This protocol provides a convenient and efficient access to a series of perfluoroalkylated aromatic aldehyde hydrazones which tolerates a wide range of functional groups on the aromatic ring, and allows the use different types of primary and secondary perfluoroalkyl iodides with up to eight carbon atoms. Furthermore, aliphatic aldehyde hydrazones and N-monosubstituted hydrazones which are unreactive in previously reported hydrazone perfluoroalkylation reactions now take part in the reaction under our reaction conditions to give a satisfactory yield of products. Stern–Volmer quenching studies and spin-trapping experiments indicated that these reactions proceed by free radical addition of the Rf radical to the azomethine atom followed by one electron oxidation of the hydrazyl radical and deprotonation of the diazenium cation.
13C-Carbamylation as a mechanistic probe for the inhibition of class D β-lactamases by avibactam and halide ions by Christopher T. Lohans; David Y. Wang; Christian Jorgensen; Samuel T. Cahill; Ian J. Clifton; Michael A. McDonough; Henry P. Oswin; James Spencer; Carmen Domene; Timothy D. W. Claridge; Jürgen Brem; Christopher J. Schofield (6024-6032).
The class D (OXA) serine β-lactamases are a major cause of resistance to β-lactam antibiotics. The class D enzymes are unique amongst β-lactamases because they have a carbamylated lysine that acts as a general acid/base in catalysis. Previous crystallographic studies led to the proposal that β-lactamase inhibitor avibactam targets OXA enzymes in part by promoting decarbamylation. Similarly, halide ions are proposed to inhibit OXA enzymes via decarbamylation. NMR analyses, in which the carbamylated lysines of OXA-10, -23 and -48 were 13C-labelled, indicate that reaction with avibactam does not ablate lysine carbamylation in solution. While halide ions did not decarbamylate the 13C-labelled OXA enzymes in the absence of substrate or inhibitor, avibactam-treated OXA enzymes were susceptible to decarbamylation mediated by halide ions, suggesting halide ions may inhibit OXA enzymes by promoting decarbamylation of acyl-enzyme complex. Crystal structures of the OXA-10 avibactam complex were obtained with bromide, iodide, and sodium ions bound between Trp-154 and Lys-70. Structures were also obtained wherein bromide and iodide ions occupy the position expected for the ‘hydrolytic water’ molecule. In contrast with some solution studies, Lys-70 was decarbamylated in these structures. These results reveal clear differences between crystallographic and solution studies on the interaction of class D β-lactamases with avibactam and halides, and demonstrate the utility of 13C-NMR for studying lysine carbamylation in solution.
Enantioselective synthesis of cyclic quaternary α-amino acid derivatives by chiral phosphoric acid catalysis by Lei Wang; Abdul Rahman; Xufeng Lin (6033-6041).
A highly enantioselective aza-Friedel–Crafts reaction of N-sulfonyl cyclic ketimines with indoles catalyzed by chiral phosphoric acids has been developed. This methodology provides an efficient and facile route to indole-containing chiral cyclic α-amino acid derivatives bearing a quaternary stereocenter in high yields and up to 98% enantioselectivity.
Stacked homodimers of substituted contorted hexabenzocoronenes and their complexes with C60 fullerene by Diana Sepúlveda; Yanfei Guan; Ulises Rangel; Steven E. Wheeler (6042-6049).
Stacking interactions involving substituted contorted hexabenzocoronene (c-HBC) with C60 were studied at the B97-D3M(BJ)/TZVPP//B97-D/TZV(2d,2p) level of theory. First, we showed that substituent effects in benzene⋯C60 complexes are uncorrelated with those in the benzene sandwich dimer, underscoring the importance of local, direct interactions in substituent effects in stacking interactions. Second, we showed that c-HBC preferentially forms stacked homodimers over complexes with C60; however, if the bowl depth of c-HBC is increased beyond 1.25 Å, the c-HBC⋯C60 complex becomes preferred over the c-HBC homodimer. Ultimately, we showed that the perfluorination of c-HBC leads to sufficient curvature to allow the c-HBC⋯C60 heterodimers to form preferentially over c-HBC homodimers, suggesting the possibility of the development of c-HBC derivatives that assemble into alternating stacks with C60.
One-step synthesis of conjugated enynenitriles from bromocyanoacetylene by Romain Ligny; Etienne S. Gauthier; Manuel Yáñez; Thierry Roisnel; Jean-Claude Guillemin; Yann Trolez (6050-6056).
The chemical reactivity of bromocyanoacetylene has been evaluated for the first time by making it react with terminal alkynes and secondary amines in the presence of bis(triphenylphosphine)palladium dichloride and copper iodide as co-catalysts. This reaction provides new conjugated enynenitriles stereoselectively in one step in variable yields.
Correction: Synthesis of l-rhamnose derived chiral bicyclic triazoles as novel sodium-glucose transporter (SGLT) inhibitors by Siddamal Reddy Putapatri; Abhinav Kanwal; Balasubramanian Sridhar; Sanjay K. Banerjee; Srinivas Kantevari (6057-6057).
Correction for ‘Synthesis of l-rhamnose derived chiral bicyclic triazoles as novel sodium-glucose transporter (SGLT) inhibitors’ by Siddamal Reddy Putapatri et al., Org. Biomol. Chem., 2014, 12, 8415–8421.
Back cover (6059-6060).