Organic & Biomolecular Chemistry (v.13, #3)
Front cover (633-634).
Contents list (635-645).
Mechanisms of imine exchange reactions in organic solvents by Maria Ciaccia; Stefano Di Stefano (646-654).
The state of the art in the mechanisms operating in imine chemistry in organic solvents is critically discussed in the present review. In particular, the reaction pathways involved in imine formation, transimination and imine metathesis in organic media are taken into account, with the aim of organizing the poor, and sometimes scattered, information available in the literature. It is shown that 4-membered cyclic transition states, either polar or apolar, can be considered a leitmotif for the chemistry of imines in organic solvents. However, it is pointed out that further investigations will be necessary to reach an adequate degree of knowledge of the mechanisms involved in such important reversible processes.
Carbocycles from donor–acceptor cyclopropanes by Huck K. Grover; Michael R. Emmett; Michael A. Kerr (655-671).
This review summarizes research directed towards the formation of carbocyclic adducts from donor–acceptor cyclopropanes. The focus of the review is on annulation and cycloaddition reactions (both inter- and intramolecularly) mediated by Lewis or protic acid, bases, or thermal conditions. Rearrangements resulting in carbocycles and those reactions mediated by transition metal catalysis have been excluded.
The synthesis of head-to-tail cyclic sulfono-γ-AApeptides by Haifan Wu; Fengyu She; Wenyang Gao; Austin Prince; Yaqiong Li; Lulu Wei; Allison Mercer; Lukasz Wojtas; Shengqian Ma; Jianfeng Cai (672-676).
We report an efficient method for the preparation of unprecedented head-to-tail cyclic sulfono-γ-AApeptides. Following this method, a number of cyclic sequences bearing two to five subunits were efficiently synthesized. In addition, the X-ray crystal structure study of a three-membered cyclic sulfono-γ-AApeptide revealed a type II β-turn-like character.
Direct oxidative coupling of thiols and benzylic ethers via C(sp3)–H activation and C–O cleavage to lead thioesters by J. Feng; M.-F. Lv; G.-P. Lu; C. Cai (677-681).
An unprecedented C–S formation method via direct oxidative C(sp3)–H bond functionalization and C–O cleavage of benzylic ethers was developed. Various thioesters including thioester structure containing drug intermediates could be achieved by this convenient, metal and base free method in satisfactory yields.
Synthesis of 3,3-dichloroindolin-2-ones from isatin-3-hydrazones and (dichloroiodo)benzene by Keith E. Coffey; Ryan Moreira; Farhana Z. Abbas; Graham K. Murphy (682-685).
Aryl- and N-substituted isatins were converted to isatin-3-hydrazones and subjected to a dichlorination reaction with PhICl2. Lewis base-catalysis was key to the reaction occurring rapidly and chemoselectively, providing 3,3-dichloroindolin-2-ones in 49–99% yield, and offering a new approach to the deoxygenative dihalogenation reaction.
Preparation of polydopamine nanocapsules in a miscible tetrahydrofuran–buffer mixture by Yun-Zhou Ni; Wen-Feng Jiang; Gang-Sheng Tong; Jian-Xin Chen; Jie Wang; Hui-Mei Li; Chun-Yang Yu; Xiao-hua Huang; Yong-Feng Zhou (686-690).
A miscible tetrahydrofuran–tris buffer mixture has been used to fabricate polydopamine hollow capsules with a size of 200 nm and with a shell thickness of 40 nm. An unusual non-emulsion soft template mechanism has been disclosed to explain the formation of capsules. The results indicate that the capsule structure is highly dependent on the volume fraction of tetrahydrofuran as well as the solvent, and the shell thickness of capsules can be controlled by adjusting the reaction time and dopamine concentration.
A mild copper-catalyzed aerobic oxidative thiocyanation of arylboronic acids with TMSNCS by Nan Sun; Liusheng Che; Weimin Mo; Baoxiang Hu; Zhenlu Shen; Xinquan Hu (691-696).
A facile and efficient transformation of arylboronic acids to their corresponding aryl thiocyanates has been successfully developed. Based on the CuCl-catalyzed oxidative cross-coupling reaction between arylboronic acids and trimethylsilylisothiocyanate (TMSNCS) under oxygen atmosphere, the transformation can be readily conducted at ambient temperature. The newly-developed protocol provided a competitive synthetic approach to aryl thiocyanates that can tolerate a broad range of reactive functional groups and/or strong electron-withdrawing groups.
Palladium-catalyzed unactivated β-methylene C(sp3)–H bond alkenylation of aliphatic amides and its application in a sequential C(sp3)–H/C(sp2)–H bond alkenylation by Gang Shan; Guiyi Huang; Yu Rao (697-701).
A palladium(ii)-catalyzed β-methylene C(sp3)–H bond alkenylation of acyclic aliphatic amides with alkenyl halides has been developed. Both (E)-olefins and (Z)-olefins can be readily accessed using this method and a possible (Z)/(E)-olefin isomerization pathway is proposed. A solvent effect-promoted sequential C(sp3)–H bond alkenylation and C(sp2)–H bond alkenylation was also studied, and can provide a convenient route to novel diene compounds.
Rhodium-catalysed arylative annulation of 1,4-enynes with arylboronic acids by Takanori Matsuda; Shoichi Watanuki (702-705).
The rhodium(i)-catalysed arylative annulation of 1,4-enynes with arylboronic acids was investigated. The reaction was found to proceed via an addition–1,4-rhodium migration–addition sequence, affording the corresponding 1,1-disubstituted 3-(arylmethylene)indanes.
Irreversible covalent modification of type I dehydroquinase with a stable Schiff base by Lorena Tizón; María Maneiro; Antonio Peón; José M. Otero; Emilio Lence; Sergio Poza; Mark J. van Raaij; Paul Thompson; Alastair R. Hawkins; Concepción González-Bello (706-716).
The irreversible inhibition of type I dehydroquinase (DHQ1), the third enzyme of the shikimic acid pathway, is investigated by structural, biochemical and computational studies. Two epoxides, which are mimetics of the natural substrate, were designed as irreversible inhibitors of the DHQ1 enzyme and to study the binding requirements of the linkage to the enzyme. The epoxide with the S configuration caused the covalent modification of the protein whereas no reaction was obtained with its epimer. The first crystal structure of DHQ1 from Salmonella typhi covalently modified by the S epoxide, which is reported at 1.4 Å, revealed that the modified ligand is surprisingly covalently attached to the essential Lys170 by the formation of a stable Schiff base. The experimental and molecular dynamics simulation studies reported here highlight the huge importance of the conformation of the C3 carbon of the ligand for covalent linkage to this type of aldolase I enzyme, revealed the key role played by the essential His143 as a Lewis acid in this process and show the need for a neatly closed active site for catalysis.
Short and efficient synthesis of fluorinated δ-lactams by Thomas J. Cogswell; Craig S. Donald; De-Liang Long; Rodolfo Marquez (717-728).
The diastereoselective synthesis of fluorinated δ-lactams has been achieved through an efficient five step process. The route can tolerate a range of functionalities, and provides a quick route for the generation of new fluorinated medicinal building blocks.
Synthesis of functionalized 2-salicyloylfurans, furo[3,2-b]chromen-9-ones and 2-benzoyl-8H-thieno[2,3-b]indoles by one-pot cyclizations of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones by Iryna Savych; Tim Gläsel; Alexander Villinger; Vyacheslav Ya. Sosnovskikh; Viktor O. Iaroshenko; Peter Langer (729-750).
Functionalized 2-salicyloylfurans and 2-benzoyl-8H-thieno[2,3-b]indoles were prepared under mild conditions by reaction of 3-halochromones with β-ketoamides and 1,3-dihydroindole-2-thiones, correspondently. The subsequent oxidative cyclization of the products resulted in formation of the corresponding furo[3,2-b]chromen-9-ones. These molecules could also be directly prepared from 3-halochromones using a one-pot protocol. The cyclization reactions reported herein are mechanistically surprising as they proceed via the oxygen and not via the (more nucleophilic) nitrogen atom of the β-ketoamide.
Exploiting the narrow gap of rearrangement between the substituents in the vicinal disubstitution reactions of diaryliodonium salts with pyridine N-sulfonamidates by Yong Wang; Ming Li; Lirong Wen; Peng Jing; Xiang Su; Chao Chen (751-763).
The vicinal disubstitution reactions of diaryliodonium salts with pyridine N-sulfonamidates to give o-pyridinium anilines were fully examined. A reaction pathway of N-arylation occurring at the amidate group followed by a radical rearrangement is proposed. The electronic effects of various substituents in this radical rearrangement were investigated.
1,1-Alkenylboration of diarylphosphino-enynes: convenient synthetic entry to vicinal P/B Lewis pairs at extended conjugated π-frameworks by Guo-Qiang Chen; Gerald Kehr; Constantin G. Daniliuc; Gerhard Erker (764-769).
Alkenylboranes R-CHCH-B(C6F5)2 undergo carbon–carbon coupling by means of 1,1-alkenylboration with diarylphosphino-enynes to give substituted conjugated hexatriene derivatives that bear a vicinal pair of B(C6F5)2 Lewis acid and PAr2 Lewis base functionalities at their central carbon portions. A series of six examples was prepared and all compounds were characterized by X-ray diffraction. Consecutive reactions of two selected examples were carried out.
Interfacial catalysis of aldol reactions by prolinamide surfactants in reverse micelles by Premkumar Rathinam Arivalagan; Yan Zhao (770-775).
l-Proline and their derivatives are among the most important class of organic catalysts. Three prolinamide surfactants were designed and synthesized. Although the surfactants carried identical catalytic groups, their headgroups contained different functionalities that affected their ability to self-assemble under reverse micelle conditions and hydrogen-bond with the reactants. The surfactant with a zwitterionic headgroup capable of strong aggregation was found to have the highest activity. The self-association of the surfactants played critical roles in the enhanced activity. The location of the catalytic groups at the surfactant/polar solvent interface also endowed unusual selectivity in the catalyzed aldol reactions.
Formation of the steroidal C-25 chiral center via the asymmetric alkylation methodology by Yu. V. Ermolovich; V. N. Zhabinskii; V. A. Khripach (776-782).
A novel approach for the preparation of steroids containing a chiral center at C-25 is reported. The key stereochemistry inducing step was asymmetric alkylation of pseudoephenamine amides of steroidal C-26 acids. The reaction proceeded with high diastereoselectivity (dr > 99 : 1). The developed methodology was successfully applied to the synthesis of (25R)- and (25S)-cholestenoic acids as well as (25R)- and (25S)-26-hydroxy brassinolides.
Self-organizing behaviour of glycosteroidal bolaphiles: insights into lipidic microsegregation by R. Xu; F. Ali-Rachedi; N. M. Xavier; S. Chambert; F. Ferkous; Y. Queneau; S. J. Cowling; E. J. Davis; J. W. Goodby (783-792).
In this article we describe work on the synthesis of bolaphile biomimics composed of glucose head groups and steroidal units linked together by a methylene chain of varying length. The condensed phases formed by self-organization of the products as a function of temperature were characterized by differential scanning calorimetry and thermal polarized light microscopy. The results of these studies show that the thermal stabilities of the lamellar mesophases formed vary linearly as a function of increasing aliphatic composition, which reflects a linear hydrophobic–hydrophilic balance with respect to transition temperatures.
A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations by Seiji Hitaoka; Hiroshi Chuman; Kazunari Yoshizawa (793-806).
A binding mechanism between human matrix metalloproteinase-12 (MMP-12) and eight arylsulfone analogs having two types of carboxylic and hydroxamic acids as the most representative zinc binding group is investigated using a quantitative structure–activity relationship (QSAR) analysis based on a linear expression by representative energy terms (LERE). The LERE–QSAR analysis quantitatively reveals that the variation in the observed (experimental) inhibitory potency among the arylsulfone analogs is decisively governed by those in the intrinsic binding and dispersion interaction energies. The results show that the LERE–QSAR analysis not only can excellently reproduce the observed overall free-energy change but also can determine the contributions of representative free-energy changes. An inter-fragment interaction energy difference (IFIED) analysis based on the fragment molecular orbital (FMO) method (FMO–IFIED) leads to the identification of key residues governing the variation in the inhibitory potency as well as to the understanding of the difference between the interactions of the carboxylic and hydroxamic acid zinc binding groups. The current results that have led to the optimization of the inhibitory potency of arylsulfone analogs toward MMP-12 to be used in the treatment of chronic obstructive pulmonary disease may be useful for the development of a new potent MMP-12 inhibitor.
Synthesis and the absolute configuration of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide as a new chiral building block for prostanoid synthesis by Beata Łukasik; Marian Mikołajczyk; Grzegorz Bujacz; Remigiusz Żurawiński (807-816).
The synthesis of both enantiomers of 4,5-dihydroxy-3-(formyl)cyclopent-2-enone acetonide (5) was accomplished in five steps starting from meso-tartaric acid (6). The key steps involved are preparation of the isopropylidene protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enone (9), resolution of the diastereoisomeric products 10 of the Horner reaction of racemic 9 with (R)-glyceraldehyde acetonide and the final regioselective ozonolysis of the exocyclic carbon–carbon double bond of the separated dienones 10 leading to both enantiomeric title compounds 5. The absolute configuration of both enantiomers was initially assigned based on the comparison of the chiroptical properties obtained from the DFT calculations with the experimental data and finally confirmed by X-ray analysis.
Rapid synthesis of isoquinolinones by intramolecular coupling of amides and ketones by Wen-Tao Wei; Yu Liu; Lin-Miao Ye; Rong-Hui Lei; Xue-Jing Zhang; Ming Yan (817-824).
Amides and ketones were intramolecularly coupled in the presence of KOt-Bu/DMF. The reaction provided good yields of a variety of isoquinolinones. A reaction mechanism of radical addition and subsequent E2-elimination is proposed.
Synthesis of (phosphonomethyl)phosphinate pyrophosphate analogues via the phospha-Claisen condensation by Fabien Gelat; Claire Lacomme; Olivier Berger; Laurent Gavara; J.-L. Montchamp (825-833).
Pyrophosphate analogues are of great importance especially for the design of biologically active molecules. The phospha-Claisen condensation allows for the rapid synthesis of (phosphonomethyl)phosphinate pyrophosphate analogues and building blocks that can be employed in numerous applications.
Sulfate recognition by a hexaaza cryptand receptor by Pedro Mateus; Rita Delgado; Vânia André; M. Teresa Duarte (834-842).
A hexamine macrobicycle with pyrrolyl spacers was evaluated as an anion receptor in its protonated forms. The protonation constants of the receptor, as well as its association constants with Cl−, NO3−, AcO−, ClO4−, H2PO4−, and SO42− were determined by potentiometry at 298.2 ± 0.1 K in H2O–MeOH (50 : 50 v/v) and at an ionic strength of 0.10 ± 0.01 M in KTsO. These studies revealed that the Hnpyrrn+ receptor has a very high effective association constant value for the SO42− at pH 4.0 (log Keff = 6.42), and it is selective for the uptake of this anion in the presence of the other studied anionic substrates. In particular, the receptor showed very high SO42−/NO3− selectivity. Using the indicator-displacement approach the receptor is able to signal the presence of sulfate by a change of color. Single crystal X-ray diffraction determination of [(H6pyrr)(SO4)(H2O)3](SO4)2·9.3H2O revealed the presence of one sulfate anion inside the receptor cavity and showed that the encapsulation of the anion is favored by an array of nine hydrogen bonding interactions, including N–H⋯O, C–H⋯O and water-mediated ones.
A thermodynamic insight into the recognition of hydrophilic and hydrophobic amino acids in pure water by aza-scorpiand type receptors by Salvador Blasco; Begoña Verdejo; Carla Bazzicalupi; Antonio Bianchi; Claudia Giorgi; Concepción Soriano; Enrique García-España (843-850).
Interactions of different hydrophilic (His, Asp, Glu,) and hydrophobic (Ala, Phe, Tyr, Trp) amino acids in water with a scorpiand aza-macrocycle (L1) containing a pyridine group in the ring and its derivative (L2) bearing a naphthalene group in the tail have been analysed by potentiometric and calorimetric measurements. Theoretical calculations corroborate that major attractive forces that hold the adduct together are hydrogen bonds and salt-bridges, even though other interactions such as π-stacking or NH+⋯π may contribute in the case of hydrophobic amino acids and L2. Calorimetric measurements indicate that the interactions between L1 and the different amino acids are principally driven by entropy, often associated with solvation/desolvation processes.
Synthesis of new unnatural Nα-Fmoc pyrimidin-4-one amino acids: use of the p-benzyloxybenzyloxy group as a pyrimidinone masking group by Abdellatif ElMarrouni; Montserrat Heras (851-858).
The p-benzyloxybenzyloxy group is used to mask the oxo function of the 4(3H)-pyrimidinone ring in the synthesis of new unnatural amino acids. The synthetic approach is based on an aromatic nucleophilic substitution reaction between 4-[4-(benzyloxy)benzyloxy]-2-(benzylsulfonyl)pyrimidine and the nucleophilic side chain of several Nα-Boc amino esters, as the key step, followed by a series of standard protecting group transformations. p-Benzyloxybenzyloxy is efficiently removed under mild acid conditions to recover the 4(3H)-pyrimidinone system.
A unified lead-oriented synthesis of over fifty molecular scaffolds by Richard G. Doveston; Paolo Tosatti; Mark Dow; Daniel J. Foley; Ho Yin Li; Amanda J. Campbell; David House; Ian Churcher; Stephen P. Marsden; Adam Nelson (859-865).
Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.
Kinetic evaluation of glucose 1-phosphate analogues with a thymidylyltransferase using a continuous coupled enzyme assay by S. M. Forget; A. Jee; D. A. Smithen; R. Jagdhane; S. Anjum; S. A. Beaton; D. R. J. Palmer; R. T. Syvitski; D. L. Jakeman (866-875).
Cps2L, a thymidylytransferase, is the first enzyme in Streptococcus pneumoniael-rhamnose biosynthesis and an antibacterial target. We herein report the evaluation of six sugar phosphate analogues selected to further probe Cps2L substrate tolerance. A modified continuous spectrophotometric assay was employed for facile detection of pyrophosphate (PPi) released from nucleotidylyltransfase-catalysed condensation of sugar 1-phosphates and nucleoside triphosphates to produce sugar nucleotides. Additionally, experiments using waterLOGSY NMR spectroscopy were investigated as a complimentary method to evaluate binding affinity to Cps2L.
Transfer of antioxidants at the interfaces of model food emulsions: distributions and thermodynamic parameters by Sonia Losada-Barreiro; Verónica Sánchez-Paz; Carlos Bravo-Díaz (876-885).
Knowledge on the driving force for the hydrophobic effect that partitions antioxidants (AOs) between the oil (O), aqueous (W) and interfacial (I) regions of food emulsions is crucial to predict their efficiency in inhibiting lipid oxidation and to preserve the organoleptic properties of lipid-based foods. Here, we have investigated the effects of temperature and surfactant volume fraction (ΦI) on the distribution of two representative AOs, the water insoluble α-tocopherol (TOC) and the oil insoluble caffeic acid (CA), in a model food emulsion composed of stripped corn oil, acidic water and the nonionic surfactant Tween 20. The distribution of the AOs is assessed in the intact emulsions by employing a well-established kinetic method based on the reaction between a hydrophobic arenediazonium ion and the AOs. The variations of the observed rate constant, kobs, with ΦI are interpreted on the grounds of the pseudophase kinetic model, which provides values for the interfacial rate constant kI and the partition constants between the aqueous–interfacial (PIW) and oil–interfacial (PIO) regions of the emulsions. From the variations of PIW, PIO and kI at a series of temperatures, we determined the Gibbs free energy, enthalpy and entropy values for the transfer of CA from the water to the interfacial (W → I) region and of TOC from the oil to the interfacial (O → I) regions of the emulsions, and the activation parameters for the reaction in the interfacial region. Activation energy values are in line with those expected for a bimolecular reaction. Results show that the W → I and O → I transfer processes are spontaneous and entropy driven.
New synthesis and biological evaluation of uniflorine A derivatives: towards specific insect trehalase inhibitors by Giampiero D'Adamio; Antonella Sgambato; Matilde Forcella; Silvia Caccia; Camilla Parmeggiani; Morena Casartelli; Paolo Parenti; Davide Bini; Laura Cipolla; Paola Fusi; Francesca Cardona (886-892).
7-Deoxy-uniflorine A (6), synthesized ex novo with a straightforward and simple strategy, and the analogues 4, 5 and 7, were evaluated as potential inhibitors of insect trehalase from Chironomus riparius and Spodoptera littoralis. All the compounds were tested against porcine trehalase as the mammalian counterpart and α-amylase from human saliva as a relevant glucolytic enzyme. The aim of this work is the identification of the simplest pyrrolizidine structure necessary to impart selective insect trehalase inhibition, in order to identify new specific inhibitors that can be easily synthesized compared to our previous reports with the potential to act as non-toxic insecticides and/or fungicides. All the derivatives 4–7 proved to be active (from low micromolar to high nanomolar range activity) towards insect trehalases, while no activity was observed against α-amylase. In particular, the natural compound uniflorine A and its 7-deoxy analogue were found to selectively inhibit insect trehalases, as they are inactive towards the mammalian enzyme. The effect of compound 6 was also analyzed in preliminary in vivo experiments. These new findings allow the identification of natural uniflorine A and its 7-deoxy analogue as the most promising inhibitors among a series of pyrrolizidine derivatives for future development in the agrochemical field, and the investigation also outlined the importance of the stereochemistry at C-6 of pyrrolizidine nucleus to confer such enzyme specificity.
Expanding the scope of fused pyrimidines as kinase inhibitor scaffolds: synthesis and modification of pyrido[3,4-d]pyrimidines by Paolo Innocenti; Hannah Woodward; Lisa O'Fee; Swen Hoelder (893-904).
Fused pyrimidine cores are privileged kinase scaffolds, yet few examples of the 2-amino-pyrido[3,4-d]pyrimidine chemotype have been disclosed in the context of kinase inhibitor programs. Furthermore, no general synthetic route has been reported to access 2-amino-pyrido[3,4-d]pyrimidine derivatives. Here we report a versatile and efficient chemical approach to this class of molecules. Our strategy involves the concise preparation of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine intermediates and their efficient derivatisation to give novel compounds with potential as kinase inhibitors.
A simple and robust preparation of N-acetylindoxyls: precursors for indigogenic substrates by Michael N. Gandy; Lindsay T. Byrne; Keith A. Stubbs (905-908).
A generalised, simple and efficient synthesis of N-acetyl-5-bromo-4-chloroindoxyl and related analogues required for the synthesis of indigogenic substrates to probe for biological activities is reported. The method is both synthetically and operationally simple and represents a significant improvement on existing methods.
Post-synthesis DNA modifications using a trans-cyclooctene click handle by Ke Wang; Danzhu Wang; Kaili Ji; Weixuan Chen; Yueqin Zheng; Chaofeng Dai; Binghe Wang (909-915).
Post-synthesis DNA modification is a very useful method for DNA functionalization. This is achieved by using a modified NTP, which has a handle for further modifications, replacing the corresponding natural NTP in polymerase-catalyzed DNA synthesis. Subsequently, the handle can be used for further functionalization after PCR, preferably through a very fast reaction. Herein we describe polymerase-mediated incorporation of trans-cyclooctene modified thymidine triphosphate (TCO-TTP). Subsequently, the trans-cyclooctene group was reacted with a tetrazine tethered to other functional groups through a very fast click reaction. The utility of this DNA functionalization method was demonstrated with the incorporation of a boronic acid group and a fluorophore. The same approach was also successfully used in modifying a known aptamer for fluorescent labelling applications.
Hydrolytic inhibition of α-chymotrypsin by 2,8,14,20-tetrakis(d-leucyl-d-valinamido)resorcarenecarboxylic acid: a spectroscopic NMR and computational combined approach by Gloria Uccello-Barretta; Federica Balzano; Federica Aiello; Letizia Vanni; Mattia Mori; Sergio Menta; Andrea Calcaterra; Bruno Botta (916-924).
The stereochemical features of 2,8,14,20-tetrakis(d-leucyl-d-valinamido)resorcarenecarboxylic acid and the N-succinyl-l-alanyl-l-alanyl-l-prolyl-l-phenylalanine-4-nitroanilide polypeptide substrate were investigated by nuclear magnetic resonance spectroscopy. Proton selective relaxation parameters gave the basis for the inhibitory activity of resorcinarene in the hydrolysis of the polypeptide substrate by α-chymotrypsin. Results showed that an interaction between the resorcinarene and α-chymotrypsin does occur, and involves the hydrophobic moiety of the macrocycle. This interaction is further reinforced by polar groups located on the side chains of the resorcinarene, whereas the macrocycle–polypeptide substrate interaction is negligible. Conformational analysis and interaction studies carried out by molecular modeling are in good agreement with the NMR data, thus providing an additional support to the rationalization of the inhibitory potential of resorcinarenes on the α-chymotrypsin activity.
Indole-based novel small molecules for the modulation of bacterial signalling pathways by Nripendra Nath Biswas; Samuel K. Kutty; Nicolas Barraud; George M. Iskander; Renate Griffith; Scott A. Rice; Mark Willcox; David StC. Black; Naresh Kumar (925-937).
Gram-negative bacteria such as Pseudomonas aeruginosa use N-acylated l-homoserine lactones (AHLs) as autoinducers (AIs) for quorum sensing (QS), a major regulatory and cell-to-cell communication system for social adaptation, virulence factor production, biofilm formation and antibiotic resistance. Some bacteria use indole moieties for intercellular signaling and as regulators of various bacterial phenotypes important for evading the innate host immune response and antimicrobial resistance. A range of natural and synthetic indole derivatives have been found to act as inhibitors of QS-dependent bacterial phenotypes, complementing the bactericidal ability of traditional antibiotics. In this work, various indole-based AHL mimics were designed and synthesized via the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and N,N′-dicyclohexylcarbodiimide (DCC) mediated coupling reactions of a variety of substituted or unsubstituted aminoindoles with different alkanoic acids. All synthesized compounds were tested for QS inhibition using a P. aeruginosa QS reporter strain by measuring the amount of green fluorescent protein (GFP) production. Docking studies were performed to examine their potential to bind and therefore inhibit the target QS receptor protein. The most potent compounds 11a, 11d and 16a showed 44 to 65% inhibition of QS activity at 250 μM concentration, and represent promising drug leads for the further development of anti-QS antimicrobial compounds.
Hydroformylation of olefins and reductive carbonylation of aryl halides with syngas formed ex situ from dehydrogenative decarbonylation of hexane-1,6-diol by Stig Holden Christensen; Esben P. K. Olsen; Jascha Rosenbaum; Robert Madsen (938-945).
A variety of primary alcohols have been investigated as convenient substrates for the ex situ delivery of carbon monoxide and molecular hydrogen in a two-chamber reactor. The gaseous mixture is liberated in one chamber by an iridium-catalysed dehydrogenative decarbonylation of the alcohol and then consumed in the other chamber in either a rhodium-catalysed hydroformylation of olefins or a palladium-catalysed reductive carbonylation of aryl halides. Hexane-1,6-diol was found to be the optimum alcohol for both reactions where moderate to excellent yields were obtained of the product aldehydes. A relatively low pressure of 1.5–2.4 bar was measured in the closed system during the two transformations.
Interactions of arene ruthenium metallaprisms with human proteins by Lydia E. H. Paul; Bruno Therrien; Julien Furrer (946-953).
Interactions between three hexacationic arene ruthenium metallaprisms, [(p-cymene)6Ru6(tpt)2(dhnq)3]6+, [(p-cymene)6Ru6(tpt)2(dhbq)3]6+ and [(p-cymene)6Ru6(tpt)2(oxa)3]6+, and a series of human proteins including human serum albumin, transferrin, cytochrome c, myoglobin and ubiquitin have been studied using NMR spectroscopy, mass spectrometry and circular dichroism spectroscopy. All data suggest that no covalent adducts are formed between the proteins and the metallaprisms. Indeed, in most cases electrostatic interactions, leading to precipitation of protein-metallaprism aggregates, have been observed. In addition, with the smallest proteins, ubiquitin, myoglobin and cytochrome c, the presence of the hexacationic arene ruthenium metallaprisms induces structural changes of the proteins, as emphasized by circular dichroism. The results suggest that proteins are certainly a biological target for these metalla-assemblies.
Back cover (955-956).