Organic & Biomolecular Chemistry (v.7, #22)

Front cover (4549-4549).

Inside front cover (4550-4550).

In the present perspective the advances and real possibilities of 1,3-dipolar cycloadditions as key steps in the total synthesis of virus inhibitors are described. Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.

Efficient synthesis of the C7-C20 subunit of amphidinolides C and F by Subham Mahapatra; Rich G. Carter (4582-4585).
Synthesis of the C7-C20 subunit of amphidinolides C and F has been accomplished utilizing a Me3Al-mediated ring opening of a vinyl iodide/allylic epoxide to establish the C12,13anti stereochemistry, an organolithium coupling/olefination sequence to construct the C9-C11 diene moiety and a sulfone alkylation/hydroxylation strategy to join the C7-C14 and C15-C20 fragments.

Olefin metathesis in carotenoid synthesis by Takayuki Kajikawa; Naoko Iguchi; Shigeo Katsumura (4586-4589).
Olefin metathesis is a powerful and widely applicable synthetic method for carbon–carbon double bond formation. However, its application to the synthesis of conjugating polyene chains has been very limited because of possible undesired side reactions. We attempted to apply this method to the synthesis of symmetrical carotenoids. In this paper, the syntheses of violaxanthin and mimulaxanthin are described using the olefin metathesis protocol.

Fluorescent detection of methylmercury by desulfurization reaction of rhodamine hydrazide derivatives by Young-Keun Yang; Sung-Kyun Ko; Injae Shin; Jinsung Tae (4590-4593).
Exposure to methylmercury causes severe damage to various tissues and organs in humans. Although a variety of fluorescent chemosensors have been exploited, only few biological monitoring systems for organomercury species have been described to date. In this report, we describe an irreversible rhodamine chemosensor for the detection of methylmercury and real-time monitoring of methylmercury in living cells and organisms.

Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartrates by Catherine F. Carter; Ian R. Baxendale; Matthew O'Brien; John B. J. Pavey; Steven V. Ley (4594-4597).
The syntheses of butane-2,3-diacetal protected tartrate derivatives are described using continuous flow processing techniques with in-line purification and I.R. analytical protocols.

A dynamic combinatorial library of metal–dye complexes was obtained by reacting aqueous solutions of the dyes Methyl Calcein Blue, Arsenazo I, and Xylenol Orange with CuCl2 and NiCl2. The mixture gave a characteristic UV-Vis response upon addition of the peptide hormones angiotensin I and angiotensin II. This allowed distinguishing pure samples of peptide hormones from mixtures. The discriminatory power of the sensor was enhanced when the several UV/Vis measurements were performed during the equilibration process of the library.

Biocatalytic oxidation by chloroperoxidase from Caldariomyces fumago in polymersome nanoreactors by H. M. de Hoog; M. Nallani; J. J. L. M. Cornelissen; A. E. Rowan; R. J. M. Nolte; I. W. C. E. Arends (4604-4610).
The encapsulation of chloroperoxidase from Caldariomyces fumago (CPO) in block copolymer polymersomes is reported. Fluorescence and electron microscopy show that when the encapsulating conditions favour self-assembly of the block copolymer, the enzyme is incorporated with concentrations that are 50 times higher than the enzyme concentration before encapsulation. The oxidation of two substrates by the encapsulated enzyme was studied: i) pyrogallol, a common substrate used to assay CPO enzymatic activity and ii) thioanisole, of which the product, (R)-methyl phenyl sulfoxide, is an important pharmaceutical intermediate. The CPO-loaded polymersomes showed distinct reactivity towards these substrates. While the oxidation of pyrogallol was limited by diffusion of the substrate into the polymersome, the rate-limiting step for the oxidation of thioansiole was the turnover by the enzyme.

Chiral C2-symmetric 3,4-bis-silyl-substituted adipic acid derivatives have been synthesised by a Mg/trimethylsilyl chloride-mediated intramolecular reductive coupling of symmetrical disiloxanes of β-silylacrylic acid N-oxazolidinone derivatives. Efficient and short syntheses of enantiomerically pure enantiomers of 2,6-dioxabicyclo[3.3.0]octane-3,7-dione have been achieved from the bis-silylated adipic acid derivatives using Fleming–Tamao oxidation as the key step.

Designing receptors that bind RNA is a challenging endeavor because of the unique and sometimes complex structure of RNA. However these structural features provide regions for ligands to bind using different types of interactions. To increase specificity and binding affinity to RNA, divalent systems have been designed which incorporate more than one binding motif into one molecule. Using this approach, we have designed a two part heteroconjugate, WKWK-Int, which contains a β-hairpin peptide covalently linked to an RNA intercalator. This heteroconjugate was designed to bind duplex RNA through intercalation and simultaneously interact with a single stranded bulge region using the side chains of the β-hairpin peptide. We have used fluorescence anisotropy experiments to show that the heteroconjugate has an increased binding affinity over either one of the individual ligands. Additionally, RNase footprinting experiments show that the structure of the peptide is necessary for the protection of one particular base in the RNA bulge region. When tested against other RNA molecules containing a stem-bulge structure, the designed heteroconjugate was found to be specific for this RNA sequence. This work provides evidence that the covalent linkage of two weak RNA ligands can greatly increase the binding affinity and also provide specificity to the binding event.

π Complexes in benzidine rearrangement by Shinichi Yamabe; Hazuki Nakata; Shoko Yamazaki (4631-4640).
By the use of DFT calculations, the title rearrangement, Ph–NH–NH–Ph (1) → H2N–C6H4–C6H4–NH2 (2), was studied for the first time. Although it is a classical reaction (found in 1862), its mechanism is almost entirely unknown. There are three complexities associated with this mechanism. The first is the various rate orders for substituted hydrazobenzenes. The second is the product distribution. The third is the result of the kinetic isotope effect which is difficult to interpret. A reaction model, 1, (H3O+)2 and (H2O)10 was used to trace the reaction path. Two hydronium ions were included, because there are two nitrogen atoms in 1. In the paths of the main reaction, 1(H+)2→2H+ + H+, transient intermediates were found. Through their conversion, the second product, diphenyline (3), was reached. For 1H+, only the Claisen shift path was found, and the π complex proposed by Dewar was not found. The absence is in accord with the kinetic result of Hammond and Shine. But the complex was revealed in the dimethoxyhydrazobenzene. Thus, while Dewar's π complex was ruled out in 1950, it has been revived by the present calculations.

Diversity-oriented synthesis of functionalized H-pyrazolo[5,1-a]isoquinolines via sequential reactions of N′-(2-alkynylbenzylidene)hydrazide is described. Bromine-mediated electrophilic cyclization, Ag-catalyzed alkyne nucleophilic addition, and palladium-catalyzed cross-coupling reaction were involved in the transformation.

Ionic liquid: an efficient and recyclable medium for synthesis of unsymmetrical diorganyl selenides promoted by InI by Senthil Narayanaperumal; Eduardo E. Alberto; Fabiano Molinos de Andrade; Eder J. Lenardão; Paulo S. Taube; Antonio L. Braga (4647-4650).
In an environmentally friendly protocol, InI was used as a reducing agent for the Se–Se bond to prepare unsymmetrical diorganyl selenides with very short reaction times, mild conditions and excellent yields using (bmim)BF4 as a recyclable solvent.

Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway by Zhi-yong Tian; Song-qiang Xie; Zi-hou Mei; Jin Zhao; Wen-yuan Gao; Chao-jie Wang (4651-4660).
Though several naphthalimide derivatives have exhibited antitumor activity in clinical trials, some issues such as toxicity prompted further structural modifications on the naphthalimide backbone. A series of naphthalimides conjugated with polyamines were synthesized to harness the polyamine transporter (PAT) for drug delivery, which was beneficial for the tumor cell selectivity. Bioevaluation in human hepatoma HepG2 cells treated with α-difluoromethylornithine (DFMO) or spermidine (Spd), human hepatoma Bel-7402 and normal QSG-7701 hepatocyte confirmed the PAT recognition and cell selectivity. In addition, the novel naphthalimide polyamine conjugate kills cells via apoptosis, and the Akt/mTOR signal pathway was first identified as the upstream cellular target through the apoptotic mechanism research. The presence of DFMO or Spd only either elevated or attenuated the cell apoptosis, but did not change the signal pathway. Collectively, the proper polyamine recognition element (i.e., homospermidine) mediated effective drug delivery via the PAT, and helped the proper cytotoxic goods (i.e., diverse naphthalimides) exert antitumor properties.

Selective recognition of tetrahedral dianions by a hexaaza cryptand receptor by Pedro Mateus; Rita Delgado; Paula Brandão; Sílvia Carvalho; Vítor Félix (4661-4673).
A hexaamine cage was synthesised in good yield by a [2+3] Schiff-base condensation followed by sodium borohydride reduction to be used as a receptor for the selective binding of anionic species. The protonation constants of the receptor, as well as its association constants with Cl, I, NO3, AcO, ClO4, H2PO4, SO42−, SeO42− and S2O32− were determined by potentiometry at 298.2 ± 0.1 K in H2O–MeOH (50 : 50 v/v) and at ionic strength 0.10 ± 0.01 mol dm−3 in KTsO. These studies revealed a remarkable selectivity for dianionic tetrahedral anions by the protonated receptor, with association constants ranging 5.03–5.30 log units for the dianionic species and 1.49–2.97 log units for monoanionic ones. Single crystal X-ray determination of [(H6xyl)(SO4)(H2O)6](SO4)2·9.5H2O showed that one sulfate anion is encapsulated into the receptor cage sited between the two 2,4,6-triethylbenzene caps establishing three N–H⋯O hydrogen bonds with two adjacent N–H binding sites and additional O–H⋯O hydrogen bonding interactions with six water of crystallization molecules. Four water molecules of the (SO4)(H2O)6 cluster interact with [H6xyl]6+ through N–H⋯O hydrogen bonds. Molecular dynamics simulations (MD) carried out with SO42− and Cl anions in H2O–MeOH (50 : 50 v/v) allowed the full understanding of anion molecular recognition, the selectivity of the protonated receptor for SO42− and the role played by the methanol and water solvent molecules.

Ni and Pd mediate asymmetric organoboron synthesis with ester functionality at the β-position by Vanesa Lillo; Michael J. Geier; Stephen A. Westcott; Elena Fernández (4674-4676).
Catalytic systems based on Ni and Pd complexes modified with chiral P-P ligands can be used in a convenient strategy for enantioselectively adding a boron unit to the β-position of α,β-unsaturated esters.

Cation localization and movement within DNA thrombin binding aptamer in solution by Marko Trajkovski; Primož Šket; Janez Plavec (4677-4684).
The thrombin binding aptamer, 15-mer oligonucleotide d[G2T2G2TGTG2T2G2], was folded into the well known antiparallel unimolecular G-quadruplex in the presence of 15NH4+ ions. Although the formed G-quadruplex is thermodynamically less stable than in the presence of K+ ions, the loop conformations and folding topology are the same. On the other hand, titration of Na+ ions into an aqueous solution of TBA resulted in the formation of one major and several minor species of G-quadruplexes. Solution-state NMR was used to localize 15NH4+ ions between the two G-quartets within the core of the structure, and to determine the equilibrium binding constant, which equals 190 M−1. No other potential cation binding sites were resolved on the time-scale of NMR spectrometer. Exchange of 15NH4+ ions between the inner binding site and bulk solution is characterized by the exchange rate constant of 1.0 s−1 at 15 °C. T4 and T13 form a noncanonical base pair, which greatly affects access of bulk ions into the cation binding site in the G-quadruplex core. G2 and G11 exhibit out of plane bending towards the two TT loops away from the bound 15NH4+ ions, which in turn exposes them to more efficient chemical exchange processes with bulk ions and water.

CCMV capsid formation induced by a functional negatively charged polymer by Inge J. Minten; Yujie Ma; Mark A Hempenius; G. Julius Vancso; Roeland J. M. Nolte; Jeroen J. L. M. Cornelissen (4685-4688).
A functional negatively charged polyelectrolyte, polyferrocenylsilane (PFS) was encapsulated in cowpea chlorotic mottle virus (CCMV) capsid proteins, yielding monodisperse particles of 18 nm in size with altered redox properties compared to the parent materials.

Development of highly sensitive and selective molecules for detection of spermidine and spermine by Daisuke Tanima; Yoko Imamura; Takeo Kawabata; Kazunori Tsubaki (4689-4694).
To establish an effective and concise procedure for determining the concentrations of spermidine and spermine, several functional molecules based on phenolphthalein and two crown loops were constructed. Host 5 with a dimethylamino group showed excellent selectivity for spermidine and spermine among other biogenic amines and high sensitivity compared with basic host 1.

Synthesis, photolysis studies and in vitro photorelease of caged TRPV1 agonists and antagonists by Michael P. Van Ryssen; Nicolaos Avlonitis; Rashid Giniatullin; Craig McDougall; James L. Carr; Megan N. Stanton-Humphreys; Emma L. A. Borgström; C. Tom A. Brown; Dmitriy Fayuk; Alexander Surin; Minna Niittykoski; Leonard Khiroug; Stuart J. Conway (4695-4707).
The synthesis of a range of caged TRPV1 agonists and antagonists is reported. The photolysis characteristics of these compounds, when irradiated with a 355 nm laser, have been studied and in all cases the desired compound was produced. Photolysis of a caged TRPV1 agonist in cultured trigeminal neurons produced responses that were consistent with the activation of TRPV1 receptors.

A novel rearrangement involving ester group migration was found in the reaction of acyl cyanides and Huisgen zwitterions, affording hydrazone derivatives at higher temperature (90 °C) and azine derivatives at lower temperature (20 °C), respectively. Interestingly, the reaction temperature is identified as a critical factor to control the final products. Presumably, the rearrangement involving ester group migration between oxygen and nitrogen atoms leads to the formation of different products.

Phenylenediamine-based bivalent glycocyclophanes: synthesis and analysis of the influence of scaffold rigidity and ligand spacing on lectin binding in cell systems with different glycomic profiles by Sabine André; Trinidad Velasco-Torrijos; Rosaria Leyden; Sebastien Gouin; Manuela Tosin; Paul V. Murphy; Hans-Joachim Gabius (4715-4725).
The conjugation of carbohydrates to synthetic scaffolds has the goal of preparing potent inhibitors of lectin binding. We herein report the synthesis of a panel of bivalent compounds (cyclophane and terephthalamide-derivatives) then used to establish the influence of scaffold flexibility on respective inhibitory potency in a medically relevant test system. Synthetic routes to two phenylenediamine-based glycocyclophanes involving Ugi reactions of glucuronic acid derivatives and subsequent ring closing metathesis are described, as are improvements for producing terephthalamide-based carbohydrate carriers. Assays were performed with human tumour cells measuring quantitatively the influence of the test compounds on fluorescent surface staining by labelled lectins. Biological evaluation using two different lines of cancer cells as well as cells with known alterations in the glycomic profile (cells treated with an inhibitor of glycan processing and a glycosylation mutant) reduced the risk of generating premature generalizations regarding inhibitor potency. Bioactivity relative to free mannose was invariably determined for the synthetic compounds. A clear trend for enhanced inhibitory properties for macrocyclic compounds compared to non-macrocyclic derivatives was discerned for one type of glycocyclophane. Herein we also document the impact of altering the spacing between the mannose residues, altering cell surface ligand density and cell-type reactivity. The applied strategy for the cell assays is proposed to be of general importance in the quest to identify medically relevant lectin inhibitors.

N-Hexyl-4-aminobutyl glycosides for investigating structures and biological functions of carbohydrates by Katsuhiko Suzuki; Akifumi Tobe; Shin Adachi; Shusaku Daikoku; Yasuko Hasegawa; Yuki Shioiri; Mariko Kobayashi; Osamu Kanie (4726-4733).
The potential applications of N-hexyl-4-aminobutyl glycosides in the mass spectrometric investigation of glycan structure and in the investigation of glycan functions were studied. Under collision-induced dissociation (CID) conditions, sodiated glycosides carrying N-hexyl-4-aminobutyl groups effectively produced a hemiacetal species (C-ions), which is important in mass-spectrometry-based structural investigation. The usefulness of N-hexyl-4-aminobutyl glycosides in biological analysis was also confirmed by obtaining a binding constant for the binding of dipyrrometheneboron difluoride C3-labeled N-hexyl-4-aminobutyl β-lactoside with an Erythrina cristagalli lectin, and by visualizing cellular organelles using a more hydrophobic BODIPY-labeled compound.

Four-fold click reactions: Generation of tetrahedral methane- and adamantane-based building blocks for higher-order molecular assemblies by Oliver Plietzsch; Christine Inge Schilling; Mariyan Tolev; Martin Nieger; Clemens Richert; Thierry Muller; Stefan Bräse (4734-4743).
A modular concept for the generation of achiral and chiral non-racemic tetrahedral tectons from common precursors was developed. The tectons presented here are based on tetraphenylmethane or 1,3,5,7-tetraphenyladamantane core structures. They are obtained through high-yielding four-fold click reactions, using either the tetraazido or the tetraalkyne precursors. In most cases, the tetratriazoles are obtained as pure products after simple washing with water and methanol. The side chains of the tectons prepared include a self-complementary DNA dimer, obtained from a 3′-azidonucleoside and a phosphoramidite. The concept allows for a variation of the “sticky ends”, leading to tecton or ligand libraries.

We report geometry-dependent cyclizations of o-alkynylaryl ketoximes and nitrones catalyzed by gold complexes. (E)-Ketoximes undergo N-attack to give isoquinoline-N-oxides. In sharp contrast, (Z)-ketoximes undergo unprecedented O-nucleophilic attack, followed by a redox cascade leading to a novel catalytic entry to isoindoles of diverse scope. The structure of an isoindole was unambiguously supported by X-ray crystallography. We demonstrated the generality of the isoindole synthesis from either (Z)-oximes or nitrones, and presented a mechanistic model of this redox cascade based on the reaction profiles of various substrates.

Exploring synthetic avenues for the effective synthesis of selenium- and tellurium-containing multifunctional redox agents by Susanne Mecklenburg; Saad Shaaban; Lalla A. Ba; Torsten Burkholz; Thomas Schneider; Britta Diesel; Alexandra K. Kiemer; Anne Röseler; Katja Becker; Jörg Reichrath; Alexandra Stark; Wolfgang Tilgen; Muhammad Abbas; Ludger A. Wessjohann; Florenz Sasse; Claus Jacob (4753-4762).
Various human illnesses, including several types of cancer and infectious diseases, are related to changes in the cellular redox homeostasis. During the last decade, several approaches have been explored which employ such disturbed redox balances for the benefit of therapy. Compounds able to modulate the intracellular redox state of cells have been developed, which effectively, yet also selectively, appear to kill cancer cells and a range of pathogenic microorganisms. Among the various agents employed, certain redox catalysts have shown considerable promise since they are non-toxic on their own yet develop an effective, often selective cytotoxicity in the presence of the ‘correct’ intracellular redox partners. Aminoalkylation, amide coupling and multicomponent reactions are suitable synthetic methods to generate a vast number of such multifunctional catalysts, which are chemically diverse and, depending on their structure, exhibit various interesting biological activities.

Synthetic dinucleotide mRNA cap analogs with tetraphosphate 5′,5′ bridge containing methylenebis(phosphonate) modification by Anna Maria Rydzik; Maciej Lukaszewicz; Joanna Zuberek; Joanna Kowalska; Zbigniew Marek Darzynkiewicz; Edward Darzynkiewicz; Jacek Jemielity (4763-4776).
An effective and facile synthesis of six novel tetraphosphate cap analogs modified with a methylenebis(phosphonate) moiety (1–6) is presented. Analogs have been rationally designed to bind tightly to the eukaryotic initiation factor 4E (eIF4E) responsible for cap binding during the initiation of translation, and have increased stability owing to resistance to enzymatic degradation. Final compounds turned out to have significantly higher association constant values (KAS) for binding to eIF4E (5–9 fold higher than standard). Four of the analogs were resistant towards enzymatic degradation by human Decapping Scavenger enzyme (DcpS). Binding studies of non-hydrolyzable analogs with DcpS revealed a broad range of KAS values for different analogs. All of the analogs were potent inhibitors of translation in a rabbit reticulocyte lysate system (RRL) and those resistant to DcpS turned out to be stable under an elongated time of preincubation while the inhibitory potency of standard was diminished in these conditions. For Anti Reverse Cap Analog (ARCA) dinucleotides (4–6), we have shown that they are effectively incorporated into mRNA and transcripts capped with these analogs undergo translation in vitro.

A series of TpxCu complexes (Tpx = hydrotrispyrazolylborate ligand) have been tested as catalysts for the decomposition of several diazoacetates and N,N-disubstituted diazoacetamides and the subsequent formation of lactones and lactams, respectively. The complexes containing the ligands TpBr3 or TpMs have provided activities and selectivities for these transformations comparable with or, in some cases, better than the well-known rhodium catalyst Rh2(OAc)4.

Direct metallation of thienopyrimidines using a mixed lithium–cadmium base and antitumor activity of functionalized derivatives by Katia Snégaroff; Frédéric Lassagne; Ghenia Bentabed-Ababsa; Ekhlass Nassar; Sidaty Cheikh Sid Ely; Stéphanie Hesse; Enrico Perspicace; Aïcha Derdour; Florence Mongin (4782-4788).
A series of thieno[2,3-d]- and thieno[3,2-d]pyrimidines have been easily synthesized using as key step a deproto-cadmiation–trapping sequence. Some of the compounds thus synthesized were screened for anticancer (cytotoxic) activities, and (S)-2-(6-iodo-2-phenylthieno[2,3-d]pyrimidin-4-ylamino)-3-phenylpropanoic acid proved to have a significant activity towards liver, human breast and cervix carcinoma cell lines.

Substitution effect on the hydrofluorination reaction of unsaturated amines in superacid HF/SbF5 by Fei Liu; Agnès Martin-Mingot; Marie-Paule Jouannetaud; Omar Karam; Sébastien Thibaudeau (4789-4797).
This paper describes the scope and limitations of the hydrofluorination reaction in superacid HF/SbF5. On the basis of experimental studies of polyfunctional substrates’ behaviour, the dramatic effect of substitution on the superelectrophilic character of ammonium–carbenium dications was emphasized. This reaction was applied to the synthesis of novel fluorinated key building blocks. Furthermore, the hydrofluorination reaction and the discovered homodimerization/fluorination reaction were applied to the synthesis of highly valued fluorinated diamines.

Back matter (4798-4798).

Back cover (4799-4800).