Organic & Biomolecular Chemistry (v.9, #4)
Front cover (949-950).
Insights in the rational design of synthetic multivalent glycoconjugates as lectin ligands by David Deniaud; Karine Julienne; Sébastien G. Gouin (966-979).
Much effort has been made during the last decade to design lectin inhibitors as therapeutics against viral and bacterial adhesion or to control biological functions. The chemical strategy adopted generally consists in the tethering of several binding epitopes on a common scaffold. The resulting multivalent glycoconjugates often display a much higher binding affinity for their targets compared to their monovalent counterparts, a phenomenon designed as the “cluster” or “multivalent effect”. Hundreds of multimeric architectures have been designed so far and some of the compounds displayed impressive gains in binding affinity or in vivo efficiency. Progress in this area is, however, hampered by the difficulty to predict the potency of the new multimeric inhibitors. This review presents the recent efforts to probe the important structural features of the synthetic multivalent glycoconjugates for a tight binding with specific lectins. We hope that the reported examples will aid the reader to design efficient multivalent ligands in a more predictable way.
Fluorescent chemodosimeter for Cys/Hcy with a large absorption shift and imaging in living cells by Mingming Hu; Jiangli Fan; Honglin Li; Kedong Song; Song Wang; Guanghui Cheng; Xiaojun Peng (980-983).
A novel molecule T1 with efficient intramolecular charge transfer was designed as a fluorescent chemodosimeter for cysteine (Cys) and homocysteine (Hcy). Upon addition of Cys/Hcy, T1 exhibited greatly enhanced fluorescence intensity as well as a large absorption peak shift (70 nm), and can be used for bioimaging of Cys/Hcy in living cells and detection in human plasma by visual color change. The detection mechanism was proved by 1H NMR, mass spectrometry analysis and Gaussian calculations.
Total synthesis of cyanolide A by Zhen Yang; Xingang Xie; Peng Jing; Gaoyuan Zhao; Jiyue Zheng; Changgui Zhao; Xuegong She (984-986).
The total synthesis of cyanolide A has been achieved in 14 steps from commercially available (S)-2-ethyloxirane, exploiting the palladium-catalyzed intramolecular alkoxycarbonylation as the key step to construct the tetrasubstituted cis-tetrahydropyran ring with high stereoselectivity.
Mechanism-based affinity capture of sirtuins by Yana Cen; Jessica N. Falco; Ping Xu; Dou Yeon Youn; Anthony A. Sauve (987-993).
The ability to probe for catalytic activities of enzymes and to detect their abundance in complex biochemical contexts has traditionally relied on a combination of kinetic assays and techniques such as western blots that use expensive reagents such as antibodies. The ability to simultaneously detect activity and isolate a protein catalyst from a mixture is even more difficult and currently impossible in most cases. In this manuscript we describe a chemical approach that achieves this goal for a unique family of enzymes called sirtuins using novel chemical tools, enabling rapid detection of activity and isolation of these protein catalysts. Sirtuin deacetylases are implicated in the regulation of many physiological functions including energy metabolism, DNA-damage response, and cellular stress resistance. We synthesized an aminooxy-derivatized NAD+ and a pan-sirtuin inhibitor that reacts on sirtuin active sites to form a chemically stable complex that can subsequently be crosslinked to an aldehyde-substituted biotin. Subsequent retrieval of the biotinylated sirtuin complexes on streptavidin beads followed by gel electrophoresis enabled simultaneous detection of active sirtuins, isolation and molecular weight determination. We show that these tools are cross reactive against a variety of human sirtuin isoforms including SIRT1, SIRT2, SIRT3, SIRT5, SIRT6 and can react with microbial derived sirtuins as well. Finally, we demonstrate the ability to simultaneously detect multiple sirtuin isoforms in reaction mixtures with this methodology, establishing proof of concept tools for chemical studies of sirtuins in complex biological samples.
Asymmetric organocatalytic Michael–α-amination sequence for the construction of a quaternary stereocenter by Alaric Desmarchelier; Jérôme Marrot; Xavier Moreau; Christine Greck (994-997).
Combination of secondary and primary amine-catalyzed organocascade Michael–α-amination is described. This sequence afforded α-hydrazino aldehydes bearing a quaternary stereocenter with high yield and excellent stereoselectivity.
Synthesis of the (−)-TAN-2483B ring system via a d-mannose-derived cyclopropane by Russell J. Hewitt; Joanne E. Harvey (998-1000).
The ring system of the fungal metabolite (−)-TAN-2483B has been synthesised, for the first time, from d-mannose, utilising a cyclopropanation/ring expansion sequence.
Imidazolium ionic liquids containing selenium: synthesis and antimicrobial activity by Eduardo E. Alberto; Luana L. Rossato; Sydney Hartz Alves; Diego Alves; Antonio L. Braga (1001-1003).
The synthesis and antimicrobial profile of imidazolium ionic liquids containing selenium are described herein. Minimum inhibitory concentration revealed that these compounds are especially active against algae, and their activity is modulated by substituents attached to the selenium moiety as well as by the counterion.
Transition metal mediated construction of pyrrole ring on 2,3-dihydroquinolin-4(1H)-one: synthesis and pharmacological evaluation of novel tricyclic heteroarenes by Mohosin Layek; Appi Reddy M.; A. V. Dhanunjaya Rao; Mallika Alvala; M. K. Arunasree; Aminul Islam; K. Mukkanti; Javed Iqbal; Manojit Pal (1004-1007).
A facile two-step method for the construction of fused pyrrole ring leading to 5-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones via C–C followed by intramolecular C–N bond forming reaction is described. In vitro pharmacological evaluation and molecular modelling studies of some of the compounds synthesized are presented.
Further investigations into the N-demethylation of oripavine using iron and stainless steel by Gaik B. Kok; Peter J. Scammells (1008-1011).
Further investigations into the direct synthesis of N-nororipavine from oripavine using iron powder under non-classical Polonovski conditions have been conducted. The stoichiometry, solvents and iron oxidation rates were found to have a dramatic effect on the rate of N-demethylation as well as product yield. Herein, we also present high-yield access to the N-demethylated product simply by employing stainless steel rather than iron powder as redox catalyst. To our knowledge, this is the first time stainless steel has been used to moderate the redox chemistry of iron in organic synthesis.
Blue fluorescent dye-protein complexes based on fluorogenic cyanine dyes and single chain antibody fragments by Kimberly J. Zanotti; Gloria L. Silva; Yehuda Creeger; Kelly L. Robertson; Alan S. Waggoner; Peter B. Berget; Bruce A. Armitage (1012-1020).
Fluoromodules are complexes formed upon the noncovalent binding of a fluorogenic dye to its cognate biomolecular partner, which significantly enhances the fluorescence quantum yield of the dye. Previously, several single-chain, variable fragment (scFv) antibodies were selected from a yeast cell surface-displayed library that activated fluorescence from a family of unsymmetrical cyanine dyes covering much of the visible and near-IR spectrum. The current work expands our repertoire of genetically encodable scFv-dye pairs by selecting and characterizing a group of scFvs that activate fluorogenic violet-absorbing, blue-fluorescing cyanine dyes, based on oxazole and thiazole heterocycles. The dye binds to both yeast cell surface-displayed and soluble scFvs with low nanomolar Kd values. These dye-protein fluoromodules exhibit high quantum yields, approaching unity for the brightest system. The promiscuity of these scFvs with other fluorogenic cyanine dyes was also examined. Fluorescence microscopy demonstrates that the yeast cell surface-displayed scFvs can be used for multicolor imaging. The prevalence of 405 nm lasers on confocal imaging and flow cytometry systems make these new reagents potentially valuable for cell biological studies.
Study of cavity size and nature of bridging units on recognition of nucleotides by cyclophanes by Prakash P. Neelakandan; Paramjyothi C. Nandajan; Baby Subymol; Danaboyina Ramaiah (1021-1029).
We synthesized a few novel cyclophanes CP-1 to CP-4 containing anthracene units linked together through different bridging and spacer groups and have investigated their interactions with various nucleosides and nucleotides. Of these systems, CP-1 and CP-3 showed selectivity for 5′-GTP and 5′-ATP as compared to other nucleotides and nucleosides, whereas negligible selectivity was observed with CP-2 and CP-4. Interestingly, CP-1, CP-2 and CP-3 exhibited significant binding interactions with the fluorescent indicator, 8-hydroxy-1,3,6-pyrene trisulfonate (HPTS), resulting in the formation of non-fluorescent complexes. Titration of these complexes with nucleosides and nucleotides resulted in the displacement of HPTS, leading to the revival of its fluorescence intensity. It was observed that 5′-GTP induced the maximum displacement of HPTS from the complex [CP-1·HPTS] with an overall fluorescence enhancement of ca. 150-fold, while 5′-ATP induced ca. 45-fold. Although the displacement of HPTS from the complexes [CP-2·HPTS] and [CP-3·HPTS] was found to be similar to that of [CP-1·HPTS], these complexes showed lesser selectivity and sensitivity. In contrast, negligible displacement of HPTS was observed from the complex [CP-4·HPTS] under similar conditions. These results indicate that CP-1, having a well-defined cavity and good electron acceptor (viologen), is capable of forming selective and stable complexes. Though CP-2 and CP-3 retain the good electron acceptor (viologen), their reduced aromatic surface and larger cavity, respectively, resulted in lesser sensitivity. In contrast, CP-4 having a large cavity and a poor acceptor (1,2-bis(pyridin-4-yl)ethene) showed negligible selectivity, thereby indicating the importance of cavity size, bridging unit and aromatic surface on biomolecular recognition properties of cyclophanes.
The formation of thymidine-based T-tetramers with remarkable structural and metal ion size effects by Qun Luo; Dayong Wu; Shixiong Liu; Daihua Tang; Yong Huang; Xinhou Liu; Fuyi Wang; Ruiyao Wang; Gang Wu (1030-1033).
We present direct ESI Q-TOF MS and X-ray evidence for remarkable structural and metal ion size effects on the formation of thymidine-based T-tetramers. The conventional H-bond acceptors on the ribose and deoxyribose may disfavor the formation of T-tetramers, and in the series of alkali metal ions, lithium did not induce T-tetramer due to its small ion size. Sodium, potassium, rubidium and caesium could produce thymidine-based T-tetramers. Furthermore, rubidium and caesium could induce T-pentamers and dimeric T-pentamers probably due to their larger ion sizes.
Tristhienylphenylamine – extended dithiafulvene hybrids as bifunctional electroactive species by Emilie Ripaud; Philippe Leriche; Nicolas Cocherel; Thomas Cauchy; Pierre Frère; Jean Roncali (1034-1040).
Extended hybrid conjugated systems based on a trithienylphenylamine core with 1, 2 and 3 peripheral dithiafulvenyl units have been synthesized and studied by cyclic voltammetry and UV-Vis. absorption spectroscopy. Theoretical calculations have also been undergone. The behaviour of these derivatives which depends on the number of dithiafulvene moieties grafted of the central core is cleared up. One polymer, obtained from derivative 3 presents polyelectrochromic properties.
Cucurbituril-resisted acylation of the anti-tuberculosis drug isoniazid via a supramolecular strategy by Hang Cong; Chun-Rong Li; Sai-Feng Xue; Zhu Tao; Qian-Jiang Zhu; Gang Wei (1041-1046).
A chemical investigation reveals that the resistance to acylation of an anti-tuberculosis drug, isoniazid is a consequent result of the inclusion or exclusion of cucurbit[n]urils (n = 6 or 7). The 1H NMR spectra analysis shows that the different interaction models of the isoniazid with the two cucurbiturils are dependent on the cavity size of the hosts. Quantum chemistry calculations with density functional theory method indicate that the interaction of the isoniazid with both cucurbiturils is through thermodynamic stabilization in both the gas phase and aqueous solution through hydrogen bonding on the portal carbonyls of the cucurbiturils. Electronic absorption titration spectra suggest the hosts and guest interact in a ratio of 1 : 1 with moderate binding constants. Acylation kinetics of isoniazid with various acylating agents in the presence of the cucurbiturils revealed that resistance is only dependent on the host–isoniazid ratio, and independent on the size of the cucurbiturils and the species of acylating agents.
Electrospray mass spectrometry for detailed mechanistic studies of a complex organocatalyzed triple cascade reaction by M. Wasim Alachraf; Peni P. Handayani; Matthias R. M. Hüttl; Christoph Grondal; Dieter Enders; Wolfgang Schrader (1047-1053).
The development of modular combinations of organocatalytic reactions into cascades has been shown to be an effective tool despite the fact that the mechanism of such a complex organocatalytic multistep cascade reaction still remains poorly understood. Here the detailed mechanistic studies of a complex organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes are reported. The investigation has been carried out using a triple quadrupole mass spectrometer with electrospray ionization. Important intermediates were detected and characterized through MS/MS studies. A detailed formation pathway is presented based on these characterized intermediates, and supporting the proposed mechanism of the formation of the substituted cyclohexene carbaldehydes.
Oxygen-promoted PdCl2-catalyzed ligand-free Suzuki reaction in aqueous media by Chun Liu; Qijian Ni; Pingping Hu; Jieshan Qiu (1054-1060).
A simple and efficient protocol has been developed for the PdCl2-catalyzed ligand-free and aerobic Suzuki reaction of aryl bromides or nitrogen-based heteroaryl bromides with arylboronic acids in good to excellent yields in aqueous ethanol. A systematic investigation on the effect of different atmospheres on the reactivity of the palladium-catalyzed Suzuki reaction has been carried out, the results show that an aerobic atmosphere demonstrates a positive effect on the reactivity of the Suzuki reaction in an aqueous media and a negative effect in a pure organic solvent, which exhibits that the water plays a crucial role for the function of the atmosphere on the palladium-catalyzed ligand-free Suzuki reaction.
Inclusion complex formation of sanguinarine alkaloid with cucurbituril: inhibition of nucleophilic attack and photooxidation by Zsombor Miskolczy; Mónika Megyesi; Gábor Tárkányi; Réka Mizsei; László Biczók (1061-1070).
The inclusion of sanguinarine, a biologically active natural benzophenanthridine alkaloid, in cucurbituril (CB7) was studied by NMR and ground-state absorption spectroscopy, as well as steady-state and time-resolved fluorescence measurements in aqueous solution. The iminium form of sanguinarine (SA+) produces very stable 1 : 1 inclusion complex with CB7 (K = 1.0 × 106 M−1), whereas the equilibrium constant for the binding of the second CB7 is about 3 orders of magnitude smaller. Marked fluorescence quantum yield and fluorescence lifetime enhancements are found upon encapsulation of SA+ due to the deceleration of the radiationless deactivation from the single-excited state, but the fluorescent properties of 1 : 1 and 1 : 2 complexes barely differ. The equilibrium between the iminium and alkanolamine forms is shifted 3.69 pK unit upon addition of CB7 as a consequence of the preferential encapsulation of the iminium form and the protection of the 6 position of sanguinarine against the nucleophilic attack by hydroxide anion. On the basis of thermodynamic cycle, about 225 M−1 is estimated for the equilibrium constant of the complexation between the alkanolamine form of sanguinarine (SAOH) and CB7. The confinement in the CB7 macrocycle can be used to impede the nucleophilic addition of OH− to SA+ and to hinder the photooxidation of SAOH.
Trifunctional 99mTc based radiopharmaceuticals: metal-mediated conjugation of a peptide with a nucleus targeting intercalator by Karel Zelenka; Lubor Borsig; Roger Alberto (1071-1078).
The development of molecular imaging agents with multiple functions has become a major trend in radiopharmaceutical chemistry. We present herein the syntheses of trifunctional compounds, combining an acridine orange (AO) based intercalator with a GRP receptor specific bombesin like peptide (BBN). Metal-mediated conjugation of these two functions via the [2 + 1] approach to the third function, the [M(CO)3]+ (M = 99mTc, Re) moiety, yielded the final trifunctional molecules. The strongly fluorescent acridine orange, a nuclear targeting agent, has been derivatised with 4-imidazolecarboxylate as a bidentate ligand and bombesin with an isonitrile group as a monodentate ligand. For cell and nuclear uptake studies, [Re(L1-BBN)(L2-Ical)(CO)3] type complexes were synthesized and characterized. For radiopharmaceutical purposes, the 99mTc analogues have been prepared in a stepwise synthesis. Fluorescence microscopy studies on PC-3 cells, bearing the BBN receptor, showed high and rapid uptake into the cytoplasm. For the bifunctional molecule, lacking the BBN peptide, no internalization was observed.
On the enantioselectivity of aziridination of styrene catalysed by copper triflate and copper-exchanged zeolite Y: consequences of the phase behaviour of enantiomeric mixtures of N-arene-sulfonyl-2-phenylaziridines by Laura Jeffs; Damien Arquier; Benson Kariuki; Donald Bethell; Philip C. Bulman Page; Graham J. Hutchings (1079-1084).
By synthesising S-2-phenyl-N-(4-nitrophenyl)aziridine from S-phenylglycinol, it has been demonstrated that the aziridination of styrene by [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane (nosyliminophenyliodinane, PhINNs) in the presence of S,S-2,2′-isopropylidene-bis(4-phenyl-2-oxazoline), catalysed by copper(ii) triflate in CH3CN solution or heterogeneously by CuHY, has predominantly an R-configuration. The enantioselectivity of the aziridination of styrene by [N-arenesulfonylimino]-phenyliodinanes catalysed by copper-exchanged zeolite Y (CuHY), in conjunction with a chiral bis-oxazoline ligand, has been re-examined. In the case of PhINNs, it is shown that the product mixture of enantiomeric aziridines, on treatment with hexane, gives rise to a solid phase of low enantiomeric excess (ee) and a solution phase of high ee. Separation of the solid phase and recrystallisation afforded a true racemate (racemic compound), which has been confirmed by X-ray crystallography. The aziridine obtained from the solution phase could be recrystallised to produce the pure enantiomer originally in excess. A consequence of the new findings is that previous reports on the enantioselectivity of copper-catalysed aziridination, both in heterogeneous and homogeneous conditions, should be regarded with caution if the analytical procedure involved HPLC with injection of the enantiomeric mixture in a hexane-rich solvent. Such a method has been used in previous work from this laboratory, but has also been used elsewhere, following the procedure developed by Evans and co-workers when the (homogeneous) copper-catalysed aziridination by PhINTs was first discovered. Evidently, the change of substituent in the benzenesulfonyl group reduces the solubility in hexane, affording a solution phase of enhanced ee.
Pyrrolic tripodal receptors for carbohydrates. Role of functional groups and binding geometry on carbohydrate recognition by Martina Cacciarini; Cristina Nativi; Martina Norcini; Samuele Staderini; Oscar Francesconi; Stefano Roelens (1085-1091).
The contribution from several H-bonding groups and the impact of geometric requirements on the binding ability of benzene-based tripodal receptors toward carbohydrates have been investigated by measuring the affinity of a set of structures toward octyl β-d-glucopyranoside, selected as a representative monosaccharide. The results reported in the present study demonstrate that a judicious choice of correct geometry and appropriate functional groups is critical to achieve the complementary hydrogen bonding interactions required for an effective carbohydrate recognition.
Mutation of isoleucine 705 of the oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae affects lanosterol's C/D-ring cyclization and 17α/β-exocyclic side chain stereochemistry by Tung-Kung Wu; Yi-Chun Chang; Yuan-Ting Liu; Cheng-Hsiang Chang; Hao-Yu Wen; Wen-Hsuan Li; Wen-Shiang Shie (1092-1097).
Site-saturated substitution in Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase at Ile705 position produced three chair-boat-chair (C–B–C) truncated tricyclic compounds, two 17α-exocyclic protosteryl intermediates, two protosteryl C-17 truncated rearranged intermediates and the normal biosynthetic product, lanosterol. These results indicated the importance of the Ile705 residue in affecting lanosterol's C/D ring stabilization including 6-6-5 tricyclic and protosteryl C-17 cations and 17α/β–exocyclic side chain stereochemistry.
The anisotropic effect of functional groups in 1H NMR spectra is the molecular response property of spatial nucleus independent chemical shifts (NICS)—Conformational equilibria of exo/endo tetrahydrodicyclopentadiene derivatives by Erich Kleinpeter; Anica Lämmermann; Heiner Kühn (1098-1111).
The inversion of the flexible five-membered ring in tetrahydrodicyclopentadiene (TH-DCPD) derivatives remains fast on the NMR timescale even at 103 K. Since the intramolecular exchange process could not be sufficiently slowed for spectroscopic evaluation, the conformational equilibrium is thus inaccessible by dynamic NMR. Fortunately, the spatial magnetic properties of the aryl and carbonyl groups attached to the DCPD skeleton can be employed in order to evaluate the conformational state of the system. In this context, the anisotropic effects of the functional groups in the 1H NMR spectra prove to be the molecular response property of spatial nucleus independent chemical shifts (NICS).
In Situ Evaluation of Lipase Performances Through Dynamic Asymmetric Cyanohydrin Resolution by Morakot Sakulsombat; Pornrapee Vongvilai; Olof Ramström (1112-1117).
A dynamic resolution process based on multiple reversible cyanohydrin formation coupled to lipase-mediated transesterification is demonstrated. The resulting process resulted in the efficient evaluation of complex lipase performances in asymmetric cyanohydrin acylate synthesis. Dynamic systems were generated and resolved in situ, and the effects of the reaction conditions could be directly monitored for the overall system. By this concept, the enzyme activity, chemo- and stereoselectivity for all involved substrates could be simultaneously evaluated.
Efficient synthesis of the anticancer β-elemene and other bioactive elemanes from sustainable germacrone by Alejandro F. Barrero; M. Mar Herrador; José F. Quílez del Moral; Pilar Arteaga; Niklas Meine; M. Carmen Pérez-Morales; Julieta V. Catalán (1118-1125).
Highly efficient preparations of anticancer β-elemene and other bioactive elemanes were carried out using the natural product germacrone as a renewable starting material. The syntheses were achieved in only 3–5 steps with excellent overall yields (43–54%). An enantioselective approach to these molecules is also described
A light-powered stretch–contraction supramolecular system based on cobalt coordinated rotaxane by Chao Gao; Xiang Ma; Qiong Zhang; Qiaochun Wang; Dahui Qu; He Tian (1126-1132).
A mechanically switchable bistable rotaxane, constituted of azobenzene modified cyclodextrins (CyDs) and a Schiff base bridged by a metallosalen unit, was designed and synthesized. 1H NOESY NMR and ICD spectra were investigated to characterize the movement process of this stretch–contraction supramolecular system. The geometries of rotaxane before and after irradiation by UV light were optimized and calculated. Coordinated with cobalt(iii) ion, the rotaxane becomes more rigid and linear, which is seen from the more obvious signals in the induced circular dichroism (ICD) and 1H NMR spectra. This type of light-powered rotaxane has favourable repeatability and exhibits a novel approach to elaborate the transformation of a light-driven molecular machine.
New hedgehog/GLI-signaling inhibitors from Adenium obesum by Midori A. Arai; Chikashi Tateno; Takashi Koyano; Thaworn Kowithayakorn; Seiichiro Kawabe; Masami Ishibashi (1133-1139).
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. We recently constructed a cell-based screening system to search for Hh/GLI signaling inhibitors from natural resources. Using our screening system, Adenium obesum was found to include Hh/GLI signaling inhibitors from our tropical plant extract libraries. Bioassay-guided fractionation of this plant extract led to the isolation of 17 cardiac glycosides (1–17), including 3 new compounds (4, 9, 16). These compounds showed strong inhibitory activities, especially the IC50 of 17 is 0.11 μM. The inhibition of GLI-related protein expression with 3, 9, 11, 15 and 17 was observed in human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited. These compounds also showed selective cytotoxicity against two cancer cell lines, with less effect against normal cells (C3H10T1/2). RT-PCT examinations showed that Ptch mRNA expression by 3, 11, 15 and 17 was inhibited.
Clicked tacrine conjugates as acetylcholinesterase and β-amyloid directed compounds by Myriam Ouberai; Kristoffer Brannstrom; Monika Vestling; Anders Olofsson; Pascal Dumy; Sabine Chierici; Julian Garcia (1140-1147).
The multifaceted nature of Alzheimer's disease (AD) has led to the development of multi-targeted compounds based on the classical AD drug, tacrine, first known to inhibit the acetylcholine-degrading enzyme acetylcholinesterase (AChE). In the present work, we explore the potentiality of multimers of tacrine in this field. The synthesis using the so-called “click chemistry” and the in vitro study of the conjugates are described. Two or four copies of the tacrine molecule are “clicked” on a constrained cyclopeptide template proven to be a convenient tool for multimeric presentation. The multimers significantly inhibit self-induced amyloid fibril formation from Aβ40 at low inhibitor to Aβ molar ratios at which the tacrine monomer is fully inactive (Thioflavin T assays and AFM observation). Moreover, they have the capacity to bind to Aβ40 fibrils (SPR assays) while retaining the AChE inhibitory activity of the parent tacrine.
Platinum-catalyzed cyclization reaction of alkynes: synthesis of azepino[3,4-b]indol-1-ones by Marina Gruit; Anahit Pews-Davtyan; Matthias Beller (1148-1159).
Novel azepino[3,4-b]indol-1-ones were synthesized from alkyne-substituted indole-2-carboxamides by catalytic intramolecular cyclization in the presence of PtCl2. The scope and limitations of this straightforward protocol are reported.
Enantiomerically pure 2-aryl(alkyl)-2-trifluoromethylaziridines: synthesis and ring opening with selected O- and N-nucleophiles by Fabienne Grellepois; Jean Nonnenmacher; Fabien Lachaud; Charles Portella (1160-1168).
We report herein the synthesis of enantiomerically pure 2-phenyl- and 2-ethyl-2-trifluoromethylaziridines by Mitsunobu-type cyclisation of the corresponding N-protected amino alcohols, and our results regarding their ring opening with selected nucleophiles. Under basic conditions, N-tosyl aziridines have been regioselectively opened at the less hindered carbon. Under acidic conditions, the regioselectivity of the attack depends on the nature of the substituent at C-2 and on the nitrogen protecting group.
Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program protobuild by Yushma Bhurruth-Alcor; Therese Røst; Michael R. Jorgensen; Christos Kontogiorgis; Jon Skorve; Robert G. Cooper; Joseph M. Sheridan; William D. O. Hamilton; Jonathan R. Heal; Rolf K. Berge; Andrew D. Miller (1169-1188).
Peroxisome proliferator activated receptors (PPARs) have been shown to have critical roles in fatty acid oxidation, triglyceride synthesis, and lipid metabolism - making them an important target in drug discovery. Here we describe the in silico design, synthesis and in vitro characterisation of a novel series of 2,5-disubstituted indoles as PPARα/γ dual agonists. PPAR activation assays are performed with known agonists diazabenzene (WY14.643), aminopyridine (BRL49653) and bisaryl (L165.041), as positive controls. All the indole compounds synthesized are found to be active PPARα and PPARγ agonists, with particular efficacy from those with 2-naphthylmethyl substitution. This is a useful demonstration of a new de novo design methodology implemented by the protobuild program and its ability to rapidly produce novel modulators for a well characterized drug target.
Synthesis of hybrid dendritic molecules with diazaphospholidine oxide grafted at the surface of octavinylsilsesquioxane (OVS) by Ge Cheng; Alexandra M. Z. Slawin; Nicolas R. Vautravers; Pascal André; Russell E. Morris; Ifor D. W. Samuel; David Cole-Hamilton (1189-1200).
A range of dendritic molecules was made using the monodentate SEMI-ESPHOS phosphine oxide ligand, which was derivatised with a series of functional groups including bromide, vinyl, allyl and terminal alkyne. Several methods to attach the resulting precursors onto octavinylsilsesquioxane (OVS), ranging from hydrosilylation, Suzuki, Heck, Grubbs or Sonogashira coupling reactions, have been investigated. Cross-metathesis of SEMI-ESPHOS oxide dendrons containing vinyl end groups with OVS catalyzed by Grubbs' catalyst was proven to be effective in the formation of precursors for dendritic molecules based on OVS.
Reveromycins Revealed: New polyketide spiroketals from Australian marine-derived and terrestrial Streptomyces spp. A case of natural products vs. artifacts by Leith Fremlin; Michelle Farrugia; Andrew M. Piggott; Zeinab Khalil; Ernest Lacey; Robert J. Capon (1201-1211).
Chemical analysis of fermentation products from two Australian Streptomyces isolates yielded all four known and twelve new examples of the rare reveromycin class of polyketide spiroketals, including hemi-succinates, hemi-fumarates and hemi-furanoates. Reveromycins were identified with the aid of HPLC-DAD-MS and HPLC-DAD-SPE-NMR methodology, and structures were assigned by detailed spectroscopic analysis. The structural and mechanistic requirements for an unprecedented hemi-succinate : ketal-succinyl equilibrium were defined and provided a basis for proposing that reveromycin 4′-methyl esters and 5,6-spiroketals were artifacts. A plausible reveromycin polyketide biosynthesis is proposed, requiring a 2-methylsuccinyl-CoA starter unit, with flexible incorporation of a C6–8 polyketide chain extension and diacid esterification units. Structure activity relationship investigations by co-metabolites were used to assess the anticancer, antibacterial and antifungal properties of reveromycins.
Copper(i)-mediated preparation of new pyrano[3′,4′:4,5]imidazo[1,2-a]pyridin-1-one compounds under mild palladium-free conditions by Zineb Bahlaouan; Mohamed Abarbri; Alain Duchêne; Jérôme Thibonnet; Nicolas Henry; Cécile Enguehard-Gueiffier; Alain Gueiffier (1212-1218).
A general and efficient Cu(i)-mediated cross-coupling and heterocyclization reaction of 3-iodoimidazo[1,2-a]pyridine-2-carboxylic acid, and terminal alkynes was developed under very mild conditions. This method allows the introduction in one pot of a third ring fused in positions 2 and 3 of the imidazo[1,2-a]pyridine core with reasonable yields and total regioselectivity. This procedure does not require the use of any expensive supplementary additives, and is palladium-free.
Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent by Takaaki Kobayashi; Mitsuhiro Arisawa; Satoshi Shuto (1219-1224).
A synthetic method for bicyclic heterocycles, such as indole, benzofuran and chromene derivatives bearing a chiral cyclopropane at the 2-position, was established using isomerization of a terminal olefin and enamide-ene or diene metathesis. This route can also be applied to chiral 2-cyclopropylquinoline synthesis (both cis and trans).
Direct transition-metal-free intramolecular C–O bond formation: synthesis of benzoxazole derivatives by Jinsong Peng; Cuijuan Zong; Min Ye; Tonghui Chen; Dewei Gao; Yufeng Wang; Chunxia Chen (1225-1230).
A direct base-mediated intramolecular carbon-oxygen bond formation has been developed without a transition-metal catalyst. In the presence of 2.0 equiv of K2CO3 in DMSO at 140 °C, the intramolecular cyclization of o-haloanilides affords benzoxazoles in high yields. A mechanism via an initial formation of a benzyne intermediate followed by nucleophilic addition to form the C–O bond has been proposed.
Rapid and practical synthesis of (−)-1-deoxyaltronojirimycin by Oskari K. Karjalainen; Ari M. P. Koskinen (1231-1236).
Herein a practical and scalable route to 1-deoxyaltronojirimycin is presented. The target is achieved in 9 steps and 43% yield featuring only two chromatographic purifications.
One-pot synthesis of donor–acceptor rotaxanes based on cryptand–paraquat recognition motif by Zhikai Xu; Lasheng Jiang; Yahui Feng; Suhui Zhang; Jidong Liang; Shaowu Pan; Yu Yang; Dengke Yang; Yuepeng Cai (1237-1243).
Two novel cryptand-based rotaxanes were synthesized by a facile one-pot reaction from three neutral precursors: easily accessible cryptand host 1 and commercially available 4,4′-bipyridine and 3,5-di-tert-butylbenzyl bromide. Their structures were confirmed by 1H NMR, 2D NMR, HRMS and X-ray analysis. Moreover, two pseudorotaxanes based on the same cryptand hosts and dibenzyl viologen guest 3 were also demonstrated both in solution and in the solid state, which are different from previously reported pseudorotaxane-like complexes formed by dimethyl viologen guest 2 and the cryptands.
Syntheses and reactivities of non-symmetrical “active ester” bi-dentate cross-linking reagents having a phthalimidoyl and acid chloride, 2-benzothiazole, or 1-benzotriazole group by Md. Chanmiya Sheikh; Shunsuke Takagi; Mebumi Sakai; Tasuya Mori; Naoto Hayashi; Tetsuo Fujie; Shin Ono; Toshiaki Yoshimura; Hiroyuki Morita (1244-1254).
We have newly synthesized the non-symmetrical “phthalimidoyl active ester” bi-dentate cross-linking reagents having an acid chloride, 2-benzothiazole, or 1-benzotriazole group (i.e., 9, 15, and 16) on the basis of the reactivity study of the “active ester” model compounds, 11–14, toward the various nucleophiles and examined their reaction selectivity towards the same nucleophiles. Then, we applied for the modification of cholesterol at the more reactive site of the bi-dentate linkers to give 3β-cholesteryl 4-(phthalimidoyloxycarbonyl)butyrate (39), and the subsequent reaction of 39 with several amines, such as benzylamine, 4-chlorobenzylamine, 2-phenylethylamine, l-phenylalanine methyl ester, or diphenylalanine benzyl ester as a protein model of the cholesterol antigen.
Back cover (1255-1256).