Organic & Biomolecular Chemistry (v.11, #35)

Front cover (5737-5737).

Inside front cover (5738-5738).

Contents list (5739-5746).

This review focuses on the chemical structure, biosynthesis and synthesis of free and glycosylated pyridinolines (Pyds), fluorescent collagen cross-links, with a pyridinium salt structure. Pyds derive from the degradation of bone collagen and have attracted attention for their use as biochemical markers of bone resorption and to assess fracture risk prediction in persons suffering from osteoporosis, bone cancer and other bone or collagen diseases. We consider and critically discuss all reported syntheses of free and glycosylated Pyds evidencing an unrevised chemistry, original and of general utility, analysis of which allows us to also support a previously suggested non-enzymatic formation of Pyds in collagen better rationalizing and justifying the chemical events.

Bioorthogonal chemistry for pre-targeted molecular imaging – progress and prospects by Laurence Carroll; Helen L. Evans; Eric O. Aboagye; Alan C. Spivey (5772-5781).
The aim of this perspective is to critically review the three most prominent bioorthogonal reactions that are used presently, on both a purely chemical level and in the context of biological systems. This includes the uses both for synthesis of therapeutic molecules, modification of large biomolecules or antibodies, and in particular, the exciting use in the field of ‘pre-targeting’, for both possible treatment and imaging technologies. We will compare the validity of each reaction when compared to others, and their usefulness in biological systems, as each methodology has clear advantages over the others in differing environments.

Total synthesis of eryvarin H and its derivatives and their biological activity as ERRγ inverse agonist by Ja Young Koo; Sangmi Oh; Seung-Rye Cho; Minseob Koh; Won-Keun Oh; Hueng-Sik Choi; Seung Bum Park (5782-5786).
Total synthesis of eryvarin H and a biological investigation of its analogues as a potential inverse agonist of ERRγ are described here. Among the 13 analogues prepared by the modular synthetic route, eryvarin H and compound 12 showed meaningful ERRγ inverse agonistic activities along with moderate selectivity over ERα and other nuclear receptors in the cell-based reporter gene assay.

A novel and simple procedure was developed for the regioselective synthesis of α-bromo (di)ketones from electron-rich epoxides via visible light photoredox catalysis. Through optimization of solvent and light source, the reaction can be rapidly achieved under mild conditions. Moreover, the possible reaction mechanism was proposed and further supported by control experiments.

Urea-catalyzed construction of oxazinanes by Andrea M. Hardman; Sonia S. So; Anita E. Mattson (5793-5797).
Highly functionalized oxazinanes are efficiently prepared through urea-catalyzed formal [3 + 3] cycloaddition reactions of nitrones and nitrocyclopropane carboxylates. The reaction system is general with respect to both the nitrocyclopropane carboxylates and nitrones enabling the preparation of a large family of oxazinanes, typically in high yield. This method affords access to enantioenriched oxazinane products through chirality transfer from enantioenriched nitrocyclopropane carboxylates.

Receptor- and ligand-based study of fullerene analogues: comprehensive computational approach including quantum-chemical, QSAR and molecular docking simulations by Lucky Ahmed; Bakhtiyor Rasulev; Malakhat Turabekova; Danuta Leszczynska; Jerzy Leszczynski (5798-5808).
Fullerene and its derivatives have potential antiviral activity due to their specific binding interactions with biological molecules. In this study fullerene derivatives were investigated by the synergic combination of three approaches: quantum-mechanical calculations, protein–ligand docking and quantitative structure–activity relationship methods. The protein–ligand docking studies and improved structure–activity models have been able both to predict binding affinities for the set of fullerene-C60 derivatives and to help in finding mechanisms of fullerene derivative interactions with human immunodeficiency virus type 1 aspartic protease, HIV-1 PR. Protein–ligand docking revealed several important molecular fragments that are responsible for the interaction with HIV-1 PR. In addition, a density functional theory method has been utilized to identify the optimal geometries and predict physico-chemical parameters of the studied compounds. The 5-variable GA-MLRA based model showed the best predictive ability (r2training = 0.882 and r2test = 0.738), with high internal and external correlation coefficients.

Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring by Julián Paños; Santiago Díaz-Oltra; María Sánchez-Peris; Jorge García-Pla; Juan Murga; Eva Falomir; Miguel Carda; Mariano Redondo-Horcajo; J. Fernando Díaz; Isabel Barasoain; J. Alberto Marco (5809-5826).
The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that all analogues are cytotoxic towards two either sensitive or resistant tumoral cell lines with similar IC50 values in each case, thus strongly suggesting that, like natural pironetin, they also display a covalent mechanism of action. Their cytotoxicity is, however, lower than that of the parent compound. This indicates that all alkyl pendants are necessary for the full biological activity, with the ethyl group at C-4 seemingly being particularly relevant. Most likely, the alkyl groups cause a restriction in the conformational mobility of the molecule and reduce the number of available conformations. This makes it more probable that the molecule preferentially adopts a shape which fits better into the binding point in α-tubulin.

Pincher ferrocene-derived cation carboxylate ion pairs in aqueous DMSO by Christie L. Beck; Stephen A. Berg; Arthur H. Winter (5827-5835).
Pincher cationic ferrocene hosts for carboxylate ion guests were synthesized and the binding constants were determined by NMR or UV-Vis titrations. These (di)cationic hosts form tight complexes with benzoate or acetate even in competitive aqueous DMSO solvent. A bis(acylguanidinium) ferrocene dication achieves a remarkable Ka of ∼106 M−1 to acetate in 9 : 1 DMSO–H2O and a Ka of 850 M−1 in neat D2O, one of the highest association constants known for a carboxylate complex exploiting only electrostatic interactions in neat water. DFT computations of the binding enthalpy are in good agreement with the experimentally determined association constants. The ferrocene backbone used in these pincher complexes may prove to be a useful semi-flexible scaffold for redox detectable/switchable self-assemblies in aqueous solutions.

Solution and thermal behaviour of novel dicationic imidazolium ionic liquids by Francesca D'Anna; H. Q. Nimal Gunaratne; Giuseppe Lazzara; Renato Noto; Carla Rizzo; Kenneth R. Seddon (5836-5846).
A new class of functionalised dicationic ionic liquids, containing a central cationic unit capped by a basic functionality (imidazole), has been synthesised. These salts have been characterised in isotropic solution using proton and 2D-NMR spectroscopy, and their thermal stability has been studied by DSC and TGA. All these novel salts contain the 1-(1-imidazolylmethyl)-3,5-di{1-(3′-octylimidazolylmethyl)}-benzene cation as a defining structural motif. Salts of both singly and doubly charged anions were prepared and, in particular, the selected monoanions (Br, [BF4], or [NTf2]) differ in size, shape and hydrogen-bonding ability, whereas the dianions differ in the nature of the spacer, such as 1,4-benzenedicarboxylate, 2,6-naphthalenedicarboxylate, 1,5- and 2,6-naphthalenedisulfonate, 1,4-butanedicarboxylate, and 1,6-hexanedicarboxylate. These ionic liquids exhibit the presence of different conformers in solution, whose distribution is affected by the nature of the anion. The nature of the anion also affects their thermal stability.

Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling by Xiao-Yu Yuan; Ding-Yi Fu; Xing-Feng Ren; Xuexun Fang; Lincong Wang; Shuxue Zou; Yuqing Wu (5847-5852).
As a new type of cathepsin K inhibitor, azadipeptide nitriles have the characteristics of proteolytic stability and excellent inhibitory activity, but they exhibit barely any satisfactory selectivity. Great efforts have focused on improving their selectivity toward cathepsin K. In this sequential study, we report the further structural optimization, synthesis, molecular modeling, and in vitro enzymatic assays of a new series of potent and selective inhibitors of cathepsin K without the P2–P3 amide linker. Significant selective improvements were achieved for cathepsin K over L, S and B, and a triaryl meta-product 13′ possessed the favorable balance between potency (Ki = 0.29 nM) and selectivity of cathepsin K over cathepsin L (320-fold), S (1784-fold) and B (8566-fold). We undertook a covalent protein–ligand docking study to explain the improved selectivity of several representative compounds. Such a selectivity improvement would be useful to avoid harmful side effects in practical applications of these compounds.

Design, synthesis, biophysical and primer extension studies of novel acyclic butyl nucleic acid (BuNA) by Vipin Kumar; Kiran R. Gore; P. I. Pradeepkumar; Venkitasamy Kesavan (5853-5865).
A novel nucleic acid analogue called acyclic (S)-butyl nucleic acid (BuNA) composed of an acyclic backbone containing a phosphodiester linkage and bearing natural nucleobases was synthesized. Next, (S)-BuNA nucleotides were incorporated in DNA strands and their effect on duplex stability and changes in structural conformation were investigated. Circular dichroism (CD), UV-melting and non-denatured gel electrophoresis (native PAGE) studies revealed that (S)-BuNA is capable of making duplexes with its complementary strands and integration of (S)-BuNA nucleotides into DNA duplex does not alter the B-type-helical structure of the duplex. Furthermore, (S)-BuNA oligonucleotides and (S)-BuNA substituted DNA strands were studied as primer extensions by DNA polymerases. This study revealed that the acyclic scaffold is tolerated by enzymes and is therefore to some extent biocompatible.

Quinoxaline derivatives with broadened absorption patterns by Lidia Marin; Laurence Lutsen; Dirk Vanderzande; Wouter Maes (5866-5876).
Quinoxaline-based semiconducting materials are currently of high interest in the field of organic photovoltaics. The number of structural variations employed has been, however, quite limited to date. In this paper we report on the synthesis of a series of quinoxaline monomers and triads with improved optical features. This was achieved by using conjugated linkers, i.e. ethenyl, butadienyl and/or aryl groups, to graft the solubilizing alkyl side chains onto the central quinoxaline core. The influence of the appended groups on the light-harvesting properties of the materials is briefly discussed.

Unprecedented regiochemical control in the formation of aryl[1,2-a]imidazopyridines from alkynyliodonium salts: mechanistic insights by Luke I. Dixon; Michael A. Carroll; Thomas J. Gregson; George J. Ellames; Ross W. Harrington; William Clegg (5877-5884).
Aryl(alkynyl)iodonium salts have been demonstrated to be valuable precursors to a diverse range of heteroaromatic ring systems including aryl[1,2-a]imidazopyridines. Successful application, using the recently described aryl(alkynyl)iodonium trifluoroacetate salts, is described, highlighting for the first time that the regioselectivity of this process is both counter-ion and concentration dependent. Studies with a carbon-13 labelled substrate established that the reactions of alkynyliodonium salts are highly complex and that multiple mechanistic processes appear to be underway simultaneously.

Synthesis of fluorinated catharanthine analogues and investigation of their biomimetic coupling with vindoline by Emerson Giovanelli; Lionel Moisan; Sébastien Comesse; Sébastien Leroux; Bernard Rousseau; Paul Hellier; Marc Nicolas; Eric Doris (5885-5891).
The syntheses of 20,20-difluorocatharanthine and congeners, starting from the naturally occurring catharanthine, are reported. The fluorinated catharanthine analogues were investigated as potential precursors to dimeric Vinca alkaloids of the vinflunine family. However, the biomimetic coupling of the fluorinated catharanthine derivatives with vindoline led to unexpected alkaloid structures, the formation of which was rationalized.

The unique hydroxylproline (Hyp)-linked O-glycan modification is a common process in hydroxyproline-rich glycoproteins (HRGPs). The modification occurs through post-translational hydroxylation at 4-position of proline residues some of which are followed by O-glycosylation at the resulting Hyp which is also found in some secreted peptide hormones such as CLAVATA3 (CLV3) of Arabidopsis thaliana plants. An active mature CLV3 is a tridecapeptide linked to β-l-Araf-(1→2)-β-l-Araf-(1→2)-β-l-Araf at a Hyp residue in the center of the peptide sequence such as Arg-Thr-Val-Hyp-Ser-Gly-Hyp(l-Arafn)-Asp-Pro-Leu-His-His-His (n = 3). We report here the synthesis of the secreted and modified CLV3 glycopeptide with all glycoforms (Araf0–3CLV3) of A. thaliana plants. A highly stereoselective β-arabinofuranosylation of Hyp derivatives as the key step of the synthesis of CLV3 glycopeptide was achieved by NAP ether-mediated IAD, which was effectively applied to the synthesis of oligoarabinosylated hydroxylproline [Hyp(l-Araf1–3)] derivatives. Fmoc-solid phase peptide synthesis was carried out using COMU as the coupling reagent for the introduction of [Hyp(l-Araf0–3)] derivatives as well as further elongation to the CLV3 glycopeptides.

KOtBu-mediated stereoselective addition of quinazolines to alkynes under mild conditions by Dan Zhao; Qi Shen; Yu-Ren Zhou; Jian-Xin Li (5908-5912).
A facile alkenylation of quinazolines with unactivated terminal alkynes has been achieved in the presence of KOtBu without the aid of any transition metal catalysts. The reaction is carried out under very mild conditions and shows a high stereoselectivity. A possible radical-based mechanism is also explored.

Chemical introduction of the green fluorescence: imaging of cysteine cathepsins by an irreversibly locked GFP fluorophore by Maxim Frizler; Ilia V. Yampolsky; Mikhail S. Baranov; Marit Stirnberg; Michael Gütschow (5913-5921).
An activity-based probe, containing an irreversibly locked GFP-like fluorophore, was synthesized and evaluated as an inhibitor of human cathepsins and, as exemplified with cathepsin K, it proved to be suitable for ex vivo imaging and quantification of cysteine cathepsins by SDS-PAGE.

Amphiphilic methyleneamino synthon through organic dye catalyzed-decarboxylative aminoalkylation by Li Chen; Chin Sheng Chao; Yuanhang Pan; Sheng Dong; Yew Chin Teo; Jian Wang; Choon-Hong Tan (5922-5925).
The utilization of a photo-induced synthon generated from N-phenyl glycine by an organic dye and visible light irradiation is disclosed. The intermediate could be coupled with either a radical or a nucleophile in a simple operation to afford several natural product-like compounds.

Ketones are prepared from aldehydes via 1-benzyl-2-(1-hydroxyalkyl)-4,5-dihydroimidazoles (adducts of the aldehydes with 1-benzyl-2-lithio-4,5-dihydroimidazoles) whereas 1-benzyl-2-(1-oxoalkyl)-4,5-dihydroimidazoles are shown to act as acyl transfer reagents via C–C bond cleavage. 4,5-Dihydroimidazolium ylides (NHCs) are intermediates in both processes, which constitute thiamine-inspired C–C bond formation and cleavage protocols.

The Pd(ii)–SDP-catalyzed first enantioselective intramolecular cyclization of α,α-disubstituted γ-alkynoic acids is described. This 5-exo-dig cyclization afforded dihydrofuran-2(3H)-ones bearing a chiral quaternary carbon center in excellent yields with enantioselectivities up to 71%. A mechanism involving palladium(ii) species is proposed to rationalize the outcome of the reaction.

Hierarchical self-assembly of amphiphilic calix[6]arene wheels and viologen axles in water by Rocco Bussolati; Pasquale Carrieri; Andrea Secchi; Arturo Arduini; Alberto Credi; Monica Semeraro; Margherita Venturi; Serena Silvi; Diana Velluto; Romina Zappacosta; Antonella Fontana (5944-5953).
We have designed and synthesized two amphiphilic calix[6]arene derivatives, CA8 and CA18, that combine the potential to act as wheel components for pseudorotaxane structures with the self-assembly features typical of surfactant molecules in aqueous solution. Their endo-cavity recognition and self-aggregation properties were compared with those of a non-amphiphilic analogue, C8. TEM, DLS, and fluorescence experiments show that in water the amphiphilic calixarenes form vesicle- and micelle-like aggregates. The size, nature and properties of such aggregates depend on the length of the alkyl chain anchored at the lower rim of the calix[6]arene skeleton, as well as on the inclusion of a molecular guest into the wheel. Specifically, the release of a fluorescent guest entrapped inside the CA8 vesicles is accelerated in the presence of dioctylviologen axles that can pierce the calixarene cavity.

An interesting sequential reaction involving Sonogashira coupling, propargyl–allenyl isomerization, intramolecular [4 + 2] cycloaddition, and bridged oxa-ring opening has been realized, providing a facile method for the synthesis of functionalized dihydroisobenzofurans from easily accessible starting materials with a decent diastereoselectivity.

Back cover (5963-5964).