Organic & Biomolecular Chemistry (v.11, #24)

Front cover (3927-3927).

Inside front cover (3928-3928).

Contents list (3929-3935).

Chemical approaches for detection and destruction of nerve agents by Dariush Ajami; Julius Rebek (3936-3942).
Since the introduction of organophosphorus (OP) compounds as nerve agents and pesticides, methods of dealing with their toxicity to humans have been intensely researched. There are studies on sensing, pretreatments, prophylactics, antidotes and therapies. There is some overlap in all of these endeavors because they have to deal with the reactivity of the phosphorus atom in various contexts. The contexts range from large spaces, the thinly spread vapors in the air, to very small spaces in the active sites of enzymes – acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) – that have reacted with the OP agent.

Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities by Chien-Hung Lin; Tsung-Che Chang; Anindya Das; Ming-Yu Fang; Hui-Chen Hung; Kai-Cheng Hsu; Jinn-Moon Yang; Mark von Itzstein; Kwok Kong T. Mong; Tsu-An Hsu; Chun-Cheng Lin (3943-3948).
A series of acylguanidine-modified zanamivir analogs were synthesized and their inhibitory activities against the NAs of avian influenza viruses (H1N1 and H3N2) were evaluated. In particular, zanamivir derivative 3j, with a hydrophobic naphthalene substituent, exhibits the best inhibitory activity against group-1 NA with an IC50 of 20 nM.

Thermal induced intramolecular [2 + 2] cycloaddition of allene-ACPs by Kai Chen; Run Sun; Qin Xu; Yin Wei; Min Shi (3949-3953).
A facile synthetic method for preparation of bicyclo[4.2.0] nitrogen heterocycles has been developed via a thermal induced intramolecular [2 + 2] cycloaddition reaction of allene-ACPs. The DFT calculations indicate that this intramolecular cycloaddition proceeds in a concerted manner and a strained small ring is essential.

Rhodamine F: a novel class of fluorous ponytailed dyes for bioconjugation by Dominik K. Kölmel; Birgit Rudat; Delia M. Braun; Christin Bednarek; Ute Schepers; Stefan Bräse (3954-3962).
Incorporation of fluorous ponytails such as polyfluorinated alkyl residues (CH2)m(CF2)nCF3 leads to a novel class of bright rhodamine-based fluorescence dyes. These dyes combine the excellent photophysical properties of the frequently used rhodamine dyes with the unique features of “light” fluorous molecules. One of those features is the possibility to separate substances utilizing fluorous solid-phase extraction (F-SPE), which is based on the specific intermolecular interaction between fluorous compounds. Thus, molecules, which are labeled with these new dyes, are not only accessible to fluorescence experiments, but can also be easily purified (via so-called FluoroFlash columns) prior to use. The dyes were bound to a cell penetrating peptoid (polycationic oligo(N-substituted) glycine) on solid supports. These conjugates were purified with F-SPE before their photophysical and biological properties were investigated.

Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides by Friedrich Erben; Dennis Kleeblatt; Marcel Sonneck; Martin Hein; Holger Feist; Thomas Fahrenwaldt; Christine Fischer; Abdul Matin; Jamshed Iqbal; Michael Plötz; Jürgen Eberle; Peter Langer (3963-3978).
Selenoindirubins and selenoindirubin-N-glycosides were prepared by the reaction of isatins and isatin-N-glycosides with 3-acetoxy-benzo[b]selenophene, respectively. While selenoindirubin-N-glycosides have not been reported before, three non-glycosylated selenoindirubins were previously reported, but without quantities, yields, scales, experimental details and spectroscopic data. In addition, the work could, in our hands, not be reproduced to prepare pure products. The present paper includes an optimized procedure for the synthesis of selenoindirubins and their complete characterization. Both selenoindirubins and selenoindirubin-N-glycosides showed antiproliferative activity in lung cancer cell lines. In melanoma cells, antiproliferative effects were further accompanied by induced apoptosis in combination with the death ligand TRAIL.

Synthesis, insecticidal activity, and structure–activity relationship (SAR) of anthranilic diamides analogs containing oxadiazole rings by Yuhao Li; Hongjun Zhu; Kai Chen; Rui Liu; Abdalla Khallaf; Xiangning Zhang; Jueping Ni (3979-3988).
A series of anthranilic diamides analogs (3–11, 16–24) containing 1,2,4- or 1,3,4-oxadiazole rings were synthesized and characterized by 1H NMR, MS and elemental analyses. The structure of 3-bromo-N-(2-(3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (18, CCDC-924454) was determined by X-ray diffraction crystallography. The insecticidal activities against Plutella xylostella and Spodoptera exigua were evaluated. The results showed that most of title compounds displayed good larvicidal activities against P. xylostella, especially compound 3-bromo-N-(4-chloro-2-methyl-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (6), which displayed 71.43% activity against P. xylostella at 0.4 μg mL−1 and 33.33% against S. exigua at 1 μg mL−1. The structure–activity relationship showed that compounds decorated with a 1,3,4-oxadiazole were more potent than compounds decorated with a 1,2,4-oxadiazole, and different substituents attached to the oxadiazole ring also affected the insecticidal activity. This work provides some hints for further structure modification and the enhancement of insecticidal activity.

Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II by Shi-Tian Zhuo; Chun-Yan Li; Ming-Hao Hu; Shuo-Bin Chen; Pei-Fen Yao; Shi-Liang Huang; Tian-Miao Ou; Jia-Heng Tan; Lin-Kun An; Ding Li; Lian-Quan Gu; Zhi-Shu Huang (3989-4005).
Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1–10 μM on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure–activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I–DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells.

A ‘dual click’ strategy for the fabrication of bioselective, glycosylated self-assembled monolayers as glycocalyx models by Carsten Grabosch; Martin Kind; Yasmin Gies; Felix Schweighöfer; Andreas Terfort; Thisbe K. Lindhorst (4006-4015).
Solid surfaces decorated with specific saccharide patterns can serve as a model for the chemically and structurally highly complex glycocalyx of eukaryotic cells. Here we present an approach based on self-assembled monolayers on gold, which are built up in a three-step manner to provide a solid basis, a biorepulsive oligoethylene glycol part, and a specific carbohydrate terminus in a modular way. Of the different reaction sequences, the one with two consecutive ‘click reactions’ (the copper(i)-catalysed 1,3-dipolar cycloaddition of alkynes with azides and the thiourea-bridging of isothiocyanates with amines) directly ‘on SAM’ results in the densest layers, as demonstrated by infrared absorption reflection spectroscopy and ellipsometry. As a ‘real life’ test, the surfaces obtained this way were used for bacterial adhesion experiments. Here the biorepulsivity of the middle part of the SAMs as well as specific binding to the carbohydrate termini could be clearly demonstrated.

The palladium-catalyzed three-component reactions of benzyl halides, activated olefins, and allyltributylstannane were successfully conducted to produce the corresponding benzylallylation products in satisfactory to high yields. The benzylallylation reaction proceeded smoothly under mild conditions in the presence of palladium nanoparticles in tetrahydrofuran.

Stereoselective cross aldol condensation of bicyclo[3.2.0]alkanones by Laurence Miesch; Tania Welsch; Michel Miesch (4025-4029).
A cross aldol reaction between [(S)-(−)] or [(R)-(+)]-benzyloxypropanal and silyl enol ethers derived from bicyclo[3.2.0]alkanones was carried out in the presence of TiCl4, leading with total stereoselectivity to a 1 : 1 mixture of enantiomerically pure diastereomers isolated in 81% overall yield. Thus, 5 stereogenic centers could be created starting from one. Furthermore, an efficient access to an enantiomerically pure tricyclo[,6]decane scaffold was possible via a 4 step reaction sequence.

Enantioselective phase-transfer catalytic α-alkylation of 2-methylbenzyl tert-butyl malonates by Min Woo Ha; Suckchang Hong; Cheonhyoung Park; Yohan Park; Jihye Lee; Mi-hyun Kim; Jihoon Lee; Hyeung-geun Park (4030-4039).
A new asymmetric synthetic method to prepare α,α-dialkylmalonates for the construction of a quaternary carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective α-alkylation of 2-methylbenzyl tert-butyl α-methylmalonates under phase-transfer catalytic conditions in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (10) afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates.

Synthesis and pharmacological characterization of new tetrahydrofuran based compounds as conformationally constrained histamine receptor ligands by Julian Bodensteiner; Paul Baumeister; Roland Geyer; Armin Buschauer; Oliver Reiser (4040-4055).
A series of tetrahydrofuran based compounds with a bicyclic core that provides conformational restriction were synthesized and investigated by radioligand displacement studies and functional [35S]GTPγS binding assays at the human histamine receptor (hHR) subtypes. The amines 8a and 8b ((1S,3R,5S,6R)- and ((1S,3S,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine), exhibited submicromolar Ki values at the hH3R with 10-fold higher affinities than their corresponding (6S)-epimers and 25- and >34-fold selectivity over the hH4R, respectively. Both compounds act as neutral antagonists at the hH3R with KB values of 181 and 32 nM, respectively. The cyanoguanidines of the imidazole series and the oxazole analogues turned out to be inactive at all hHR subtypes.

The reaction between 5-(4-pyridyl)dipyrrylmethane and aromatic aldehydes affords meso-arylsubstituted trans-A2B2 di(4-pyridyl)porphyrins which are key building blocks in the metal-mediated self-assembling of supramolecular structures. A careful optimization of the reaction conditions allowed us to obtain 5,15-diphenyl-10,20-di(4-pyridyl)porphyrin (P1), and two analogues bearing on the meso-phenyl substituents two dipropyl- (P4) or dihexyl-alkyl chains (P5), with yields ranging from 53 to 63%. Porphyrin P1 reacts with Re(CO5)Br to give the expected 4 + 4 Re(i)–porphyrin metallacycle which has been fully characterized by means of infrared, NMR and UV-Vis (absorption and emission) spectroscopies and by guest inclusion studies. Unexpectedly the addition of alkyl chains to the porphyrin fragment, which increase the solubility of the porphyrin in organic solvents, has the opposite effect on the adduct with Re(i). Indeed, the reaction between Re(CO5)Br and porphyrins P4,5 gives very insoluble materials, hampering their complete characterization.

O-Benzoxazolyl imidates as versatile glycosyl donors for chemical glycosylation by Swati S. Nigudkar; Archana R. Parameswar; Papapida Pornsuriyasak; Keith J. Stine; Alexei V. Demchenko (4068-4076).
Herein, we report a new class of glycosyl donors, benzoxazolyl imidates, for chemical glycosylation. The O-benzoxazolyl (OBox) leaving group was designed with an aim to compare the relative reactivity and stability of similarly structured S-benzoxazolyl (SBox) glycosides (thioimidates) developed in our lab and glycosyl trichloroacetimidates (TCAI, O-imidates) developed by Schmidt. Novel OBox donors can be activated under catalytic conditions and provided excellent yields in glycosylation. The OBox imidates were found to be more reactive than either SBox or TCAI donors. The high reactivity profile was confirmed in direct competitive experiments and was found beneficial for HPLC-assisted solid-phase synthesis.

Dibenzotetraaza[14]annulene–adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences by Marijana Radić Stojković; Marko Škugor; Sanja Tomić; Marina Grabar; Vilko Smrečki; Łukasz Dudek; Jarosław Grolik; Julita Eilmes; Ivo Piantanida (4077-4085).
Among three novel DBTAA derivatives only the DBTAA–propyl–adenine conjugate 1 showed recognition of the consecutive oligo dT sequence by increased affinity and specific induced chirooptical response in comparison to other single stranded RNA and DNA; whereby of particular importance is the up until now unique efficient differentiation between dT and rU. At variance, its close analogue DBTAA–hexyl–adenine 2 did not reveal any selectivity between ss-DNA/RNA pointing out the important role of steric factors (linker length); moreover non-selectivity of the reference compound (3, lacking adenine) stressed the importance of adenine interactions in the 1 selectivity.

Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria by Barbara Richichi; Anne Imberty; Emilie Gillon; Rosa Bosco; Ieva Sutkeviciute; Franck Fieschi; Cristina Nativi (4086-4094).
Burkholderia ambifaria is a bacterium member of the Burkholderia cepacia complex (BCC), a closely related group of Gram-negative bacteria responsible for “cepacia syndrome” in immunocompromised patients. B. ambifaria produces BambL, a fucose-binding lectin that displays fine specificity to human fucosylated epitopes. Here, we report the first example of a synthetic ligand able to selectively bind, in the micromolar range, the pathogen-lectin BambL. The synthetic routes for the preparation of the α conformationally constrained fucoside are described, focusing on a totally diastereoselective inverse electron demand [4 + 2] Diels–Alder reaction. Isothermal titration calorimetry (ITC) demonstrated that this compound binds to the pathogen-associated lectin BambL with an affinity comparable to that of natural fucose-containing oligosaccharides. No binding was observed by LecB, a fucose-binding lectin from Pseudomonas aeruginosa, and the differences in affinity between the two lectins could be rationalized by modeling. Furthermore, SPR analyses showed that this fucomimetic does not bind to the human fucose-binding lectin DC-SIGN, thus supporting the selective binding profile towards B. ambifaria lectin.

An intramolecular cyclization of 2-(gem-dibromovinyl)phenols(thiophenols) to give 2-bromobenzofurans(thiophenes) in the presence of a trace amount of Cu (0.0064 mol%, 25 ppm) has been developed. The reaction provides the desired products in excellent yields under fluoride-free and mild reaction conditions and with a TON (turnover number) of up to 1.5 × 104.

A transition metal-free tandem process to pyridazinopyrido[3,2-f][1,4]thiazepine-diones via Smiles rearrangement by Xiaoyi Niu; Bingchuan Yang; Yanqiu Li; Shuai Fang; Zixiao Huang; Caixia Xie; Chen Ma (4102-4108).
A transition metal-free methodology for the synthesis of pyridazinopyrido[3,2-f][1,4]thiazepine-diones was studied. The construction of this tricyclic system went through a one-pot coupling/Smiles rearrangement/cyclization process. The high yields of pure products were obtained through simple recrystallization.

Biocompatible, multifunctional, and well-defined OEG-based dendritic platforms for biomedical applications by Lorena Simón-Gracia; Daniel Pulido; Chantal Sevrin; Christian Grandfils; Fernando Albericio; Miriam Royo (4109-4121).
Given the growing importance of drug and gene delivery systems, imaging agents, biosensors, and theranostics, there is a need to develop new multifunctional and biocompatible platforms. Here we synthesized and fully characterized a family of novel multifunctional and completely monodisperse dendritic platforms. Our synthetic methodology, based on compatible protecting groups and the attachment of monodisperse triethylene glycol units, allows the control of the generation and differentiation of terminal groups, thus giving rise to multifunctional and perfectly-defined products. A family of dendrons was synthesized and four distinct dendritic structures were chosen from the family in order to determine the effect of the generation and surface groups on their biocompatibility. The stability in serum, cytotoxicity, and hemocompatibility of these products were studied. Our results indicate that these non-toxic, hemocompatible, non-immunogenic, stable and versatile scaffolds may be very interesting candidates for biomedical applications.

Back cover (4123-4124).