Organic & Biomolecular Chemistry (v.15, #37)

Front cover (7717-7717).

Inside front cover (7718-7718).

Contents list (7719-7728).

Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery by Adrian Whitty; Lauren A. Viarengo; Mengqi Zhong (7729-7735).
We discuss progress towards addressing three key questions pertaining to the design of screening libraries of synthetic non-peptidic macrocycles (MCs) for drug discovery: What structural and physicochemical properties of MCs maximize the likelihood of achieving strong and specific binding to protein targets? What features render a protein target suitable for binding MCs, and can this information be used to identify suitable targets for inhibition by MCs? What properties of synthetic MCs confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability? We additionally discuss how the criteria that define a meaningful MC screening hit are linked to the size of the screening library and the synthetic methodology employed in its preparation.

An efficient, metal-free synthesis of unusual α-keto γ-amino esters from α-amino acids is achieved by a radical scission–oxidation–addition of silyloxy acrylates procedure, where no purification of the reaction intermediates is needed. This protocol can be applied to the selective modification of the C-terminal position in peptides to give α,γ-hybrids.

Iron-catalyzed intermolecular cycloaddition of diazo surrogates with hexahydro-1,3,5-triazines by Pei Liu; Chenghao Zhu; Guangyang Xu; Jiangtao Sun (7743-7746).
We report here an unprecedented iron-catalyzed cycloaddition reaction of diazo surrogates with hexahydro-1,3,5-triazines, providing five-membered heterocycles in moderate to high yields under mild reaction conditions. This cycloaddition features C–N and C–C bond formation using a cheap iron catalyst. Importantly, different to our former report on a gold-catalyzed system, both donor/donor and donor/acceptor diazo substrates are tolerated in this iron-catalyzed protocol.

A novel aryl-triazole foldamer incorporating a 1,8-naphthalimide motif was designed and synthesized. 1H NMR, UV-vis and fluorescence spectroscopic titration experiments with halide anions (Cl, Br, I) demonstrated that the π–π stacking interaction of 1,8-naphthalimide building blocks could largely enhance the folding and anion binding of the foldamer.

Enantioselective electrophilic cyanation of β-keto amides catalysed by a cinchona organocatalyst by Pran Gopal Karmaker; Jiashen Qiu; Di Wu; Mengmeng Reng; Zhuo Yang; Hongquan Yin; Fu-Xue Chen (7753-7757).
An operationally simple protocol for the enantioselective electrophilic α-cyanation of β-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric α-cyanation reaction.

Novel spirocyclic systems via multicomponent aza-Diels–Alder reaction by Sabin Llona-Minguez; Adam Throup; Emilie Steiner; Molly Lightowler; Sandra Van der Haegen; Evert Homan; Lars Eriksson; Pål Stenmark; Annika Jenmalm-Jensen; Thomas Helleday (7758-7764).
Here we present a two-step diastereoselective methodology building on a multicomponent aza-Diels–Alder reaction. Using previously unexplored cyclic ketones, heterocyclic amines and cyclopentadiene derivatives, we obtained novel spiro-heterocyclic frameworks at the interphase between “drug-like” molecules and natural products.

Red-emissive fluorescent probes have been developed by integration of quinoline blue or thiazole red as the base surrogate into triplex-forming PNAs, allowing selective sensing of a sequence of double-stranded RNA.

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring by Adel A. Rashad; Kriti Acharya; Ann Haftl; Rachna Aneja; Alexej Dick; Andrew P. Holmes; Irwin Chaiken (7770-7782).
HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the discovery of cyclic peptide triazoles (cPTs) that retain the HIV-1 irreversible inactivation functions of the parent linear peptides (PTs) and have massively increased proteolytic resistance. Here, in an initial structure–activity relationship investigation, we evaluated the effects of variations in key structural and functional components of the cPT scaffold in order to produce a platform for developing next-generation cPTs. Some structural elements, including stereochemistry around the cyclization residues and Ile and Trp side chains in the gp120-binding pharmacophore, exhibited relatively low tolerance for change, reflecting the importance of these components for function. In contrast, in the pharmacophore-central triazole position, the ferrocene moiety could be successfully replaced with smaller aromatic rings, where a p-methyl-phenyl methylene moiety gave cPT 24 with an IC50 value of 180 nM. Based on the observed activity of the biphenyl moiety when installed on the triazole ring (cPT 23, IC50∼ 269 nM), we further developed a new on-resin synthetic method to easily access the bi-aryl system during cPT synthesis, in good yields. A thiophene-containing cPT AAR029N2 (36) showed enhanced entropically favored binding to Env gp120 and improved antiviral activity (IC50∼ 100 nM) compared to the ferrocene-containing analogue. This study thus provides a crucial expansion of chemical space in the pharmacophore to use as a starting point, along with other allowable structural changes, to guide future optimization and minimization for this important class of HIV-1 killing agents.

Carbazole-based BODIPYs 1–6 with several different substituents at the boron atom site were synthesized. These dyes fluoresced in the solid state, and 3a with phenylethynyl groups exhibited a red-shifted and broad fluorescence spectrum, which suggested an excimer emission. Its derivatives 3b–n were synthesized, and the relationship between the solid-state emission and crystal packing was investigated. The X-ray crystal structures revealed cofacial dimers that might form excimers. From the structural optimization results, we found that the introduction of mesityl groups hindered intermolecular access and led to reduced interactions between the dimers. In addition, the red-shifted excimer fluorescence suppressed self-absorption, and dyes with ethynyl groups showed solid-state fluorescence in the vis/NIR region.

In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC). We designed a new biphenyl-2,6-dicarboxylate monomer, I, with the goal of creating a buried salt bridge with Kme2 inside a synthetic receptor. Indeed, incorporation of I into the receptor A2I resulted in a receptor with 32-fold enhancement in binding affinity, which represents the highest affinity receptor for Kme2 in the context of a peptide to date and is tighter than most Kme2 reader proteins. It also exhibits a ∼2.5-fold increase in preference for Kme2 vs. Kme3 relative to the parent receptor, A2B. This work provides insight into effective strategies for binding hydrophilic, cationic guests in water and is an encouraging result toward a synthetic receptor that selectively binds Kme2 over other methylation states of lysine.

A one-pot multicomponent approach to a new series of morphine derivatives and their biological evaluation by Jiaan Shao; Richard A. Houghten; Colette T. Dooley; Margret Cazares; Jay P. McLaughlin; Shainnel O. Eans; Michelle L. Ganno; Michelle R. Hoot; Marc A. Giulianotti; Yongping Yu (7796-7801).
A novel and facile domino reaction has been developed to synthesize a variety of new derivatives from hydromorphone, amines and paraformaldehyde in good yields in a catalyst-free fashion with high atom efficiency. The products show a mixed MOR/DOR biological characteristic which makes them valuable for further study as opioid analgesics.

Synthesis of lipo-chitooligosaccharide analogues and their interaction with LYR3, a high affinity binding protein for Nod factors and Myc-LCOs by Nathan Berthelot; Antoine Brossay; Virginie Gasciolli; Jean-Jacques Bono; Aurélie Baron; Jean-Marie Beau; Dominique Urban; François-Didier Boyer; Boris Vauzeilles (7802-7812).
Lipo-chitotetrasaccharide analogues where one central GlcNAc residue was replaced by a triazole unit have been synthesized from a derivative obtained by chitin depolymerization and a functionalized N-acetyl-glucosamine via the copper-catalyzed azide–alkyne cycloaddition. Their evaluation in a binding assay using LYR3, a putative lipo-chitooligosaccharide receptor in Medicago truncatula, shows a complete loss of binding.

Gold-catalyzed intramolecular cyclization/condensation sequence: synthesis of 1,2-dihydro[c][2,7]naphthyridines by Kommuru Goutham; Veerabhushanam Kadiyala; Balasubramanian Sridhar; Galla V. Karunakar (7813-7818).
An efficient gold-catalyzed synthetic protocol for the construction of 1,2-dihydro[c][2,7]naphthyridines from 2-aminophenyl prop-2-yn-1-yl enaminones has been developed. In this organic transformation new C–C and C–N bond formations occur via 6-endo-dig cyclization and condensation. 1,2-Dihydro[c][2,7]naphthyridine derivatives were obtained in good to excellent yields in a one-pot synthesis at ambient temperature.

Catalyst-free synthesis of 3-sulfone nitrile from sulfonyl hydrazides and acrylonitrile in water by Wei Li; Lingfeng Gao; Wenyun Zhuge; Xu Sun; Gengxiu Zheng (7819-7823).
A novel catalyst-free sulfonation reaction for synthesizing 3-sulfone nitrile compounds from sulfonyl hydrazides and acrylonitriles in water, without any metal catalyst, ligand or organic solvent, was demonstrated. This catalyst-free protocol provides a new synthetic method for the construction of 3-sulfone nitrile compounds with excellent yields. The D2O experiment adequately proved that the catalyst-free sulfonation reaction occurs via a Michael addition mechanism and that the hydrogen of 3-sulfone nitrile comes from water.

Cerium-catalyzed, oxidative synthesis of annulated, tetrasubstituted dihydrofuran-derivatives by Irina Geibel; Marc Schmidtmann; Jens Christoffers (7824-7829).
Densely functionalized, annulated dihydrofuran derivatives are prepared by a cerium-catalyzed aerobic oxidation reaction. The operationally simple transformation is environmentally and economically benign, since the precatalyst CeCl3·7H2O is non-toxic and inexpensive and the oxidant is simply dioxygen from air. Starting materials are β-oxoesters and silylenolethers, and the latter are derived from acetoacetate or acetylacetone. The reaction sequence is performed in one flask and consists of α-oxidation and Mukaiyama aldol reaction. Apart from tetrahydrocyclopenta[b]furan derivatives one example of a tetrahydrofuro[3,4-b]furan and one tetrahydro-3aH-furo[2,3-c]pyrrole derivative are prepared.

The Pd-catalyzed, CN-directed unsymmetrical synthesis of 2,4′-bithiophenes via an unprecedented homocoupling reaction is described. The NH2/CN/SMe arrangement breaks the routine. The cooperative performance of the functional groups in thiophenes would open up a new vision in the field of metal catalysis homocoupling reactions by joining the electrophilic and nucleophilic motifs of the substrate. Furthermore, it is found that the α-chelating effect of the carbonyl group in amino thiophene offers a new class of synthetic protocols for C–N cross-coupling with arylboronic acids. The bidentate N,O-chelation provides a series of advantages such as copper-catalyzed, ligand- and base-free under open-flask conditions. Interestingly, the combination of the C–N cross-coupling/homocoupling reactions in a domino fashion led to the bithiophene adducts featuring the C(Ar)–N bond cleavage in the nitrogen that bridged between the two thiophene units.

Why can a gold salt react as a base? by Mariarosa Anania; Lucie Jašíková; Juraj Jašík; Jana Roithová (7841-7852).
This study shows that gold salts [(L)AuX] (L = PMe3, PPh3, JohnPhos, IPr; X = SbF6, PF6, BF4, TfO, Tf2N) act as bases in aqueous solutions and can transform acetone to digold acetonyl complexes [(L)2Au2(CH2COCH3)]+ without any additional base present in solution. The key step is the formation of digold hydroxide complexes [(L)2Au2(OH)]+. The kinetics of the formation of the digold complexes and their mutual transformation is studied by electrospray ionization mass spectrometry and the delayed reactant labelling method. We show that the formation of digold hydroxide is the essential first step towards the formation of the digold acetonyl complex, the reaction is favoured by more polar solvents, and the effect of counter ions is negligible. DFT calculations suggest that digold hydroxide and digold acetonyl complexes can exist in solution only due to the stabilization by the interaction with two gold atoms. The reaction between the digold hydroxide and acetone proceeds towards the dimer {[(L)Au(OH)]·[(L)Au(CH3COCH3)]+}. The monomeric units interact at the gold atoms in the perpendicular arrangement typical of the gold clusters bound by the aurophilic interaction. The hydrogen is transferred within the dimer and the reaction continues towards the digold acetonyl complex and water.

The fluorescently responsive 3-(naphthalen-1-ylethynyl)-3-deaza-2′-deoxyguanosine discriminates cytidine via the DNA minor groove by Azusa Suzuki; Masaki Yanagi; Takuya Takeda; Robert H. E. Hudson; Yoshio Saito (7853-7859).
A new environmentally responsive fluorescent nucleoside, 3-(naphthalen-1-ylethynyl)-3-deaza-2′-deoxyguanosine (3nzG), has been synthesized. The nucleoside, 3nzG, exhibited solvatochromic properties and when introduced into ODN probes it was able to recognize 2′-deoxycytidine in target strands by a distinct change in its emission wavelength through probing microenvironmental changes in the DNA minor groove. Thus, 3nzG has the potential for use as a fluorescent probe molecule for micro-structural studies of nucleic acids including the detection of single-base alterations in target DNA sequences.

Iron-dependent enzymes and biomimetic iron complexes can catalyze the ring cleavage of very inert, aromatic compounds. The mechanisms of these transformations and the factors that lead either to extradiol cleavage or intradiol cleavage have not been fully understood. By using density functional theory we have elucidated the mechanism of the catalytic cycle for two biomimetic complexes, and explained the difference in the experimentally obtained products.

In this paper, we developed a tandem of two carbon–carbon bond-forming reactions to chemically diversify the libraries of peptides displayed on a bacteriophage. The Wittig reaction of a biotin-ester from a stabilized phosphorane ylide with model peptides containing N-terminal glyoxal exhibits reaction rates of 0.07 to 5 M−1 s−1 in water at pH 6.5–8. The log(k) scaled linearly with pH from pH 6 to 8; above pH 9 the reaction is accompanied by the hydrolysis of the ester functionality. Capture of the phage displaying the biotinylated product by streptavidin beads confirmed the rate of this reaction in a library of 108 peptides (k = 0.23 M−1 s−1 at pH = 6.5) and also confirmed the regioselectivity of this modification. Olefins introduced into the Wittig reaction can act as Michael acceptors: addition of glutathione, cysteamine, and DYKDDDDKC (“FLAG-Cys”) peptide occurs with k = 0.12–4.1 M−1 s−1 at pH 7.8. Analogous reactions with the DYKDDDDKC peptide take place on phage-displayed peptides modified via the Wittig reaction. This reaction is manifested as a progressive emergence of a FLAG-epitope on the phage and detected by the capture of this phage using an anti-FLAG antibody. Olefins introduced into the Wittig reaction also act as dienophiles in the Diels–Alder reaction with cyclopentadiene. The conversion of the dienophile to norbornene-like adducts on the phage was observed by monitoring the disappearance of the thiol-reactive olefin on the phage. This report broadens the reaction scope of genetically-encoded peptide libraries displayed on the phage, expanding the structural diversity of these platforms and increasing their potential to be used in screening against important protein targets. The possibility of monitoring tandem reactions by the use of different labels illustrates the feasibility of obtaining highly functionalized peptides with chemical motifs impossible to achieve using conventional translational machinery.

DBU-mediated [4 + 1] annulations of donor–acceptor cyclopropanes with carbon disulfide or thiourea to form 2-aminothiophene-3-carboxylate derivatives have been discovered. This reaction proceeds via the ring opening of donor–acceptor cyclopropanes to produce a 2-(iminomethylene)but-3-enoate intermediate, followed by the attack of an S-nucleophile for regioselective intermolecular nucleophilic addition, intramolecular S-nucleophilic addition, and final aromatization. A variety of functional groups could be tolerated under the reaction conditions.

Recently we reported the aromatic Claisen rearrangements of benzyl ketene acetals, which form one of the few examples of aromatic Claisen rearrangements involving benzyl vinyl ethers (as opposed to allyl aryl ethers, which are the usual substrates for aromatic Claisen rearrangements). Theoretical calculations predict that these rearrangements proceed via a concerted [3,3]-sigmatropic transition state, which is similar in geometry to the TS for the Claisen rearrangement of an allyl aryl ether but has a 4 kcal mol−1 higher barrier. The effects of donor (OMe) and acceptor (CN) substituents on the kinetics of the [3,3]-rearrangement mirror those reported for allyl vinyl ethers: the largest substituent effects are seen for 1-OMe, 2-OMe, 2-CN, and 4-CN substituents, which lower the barrier by 5–9 kcal mol−1. Substituents on the aromatic ring have smaller effects on the barrier (≤2 kcal mol−1). The regioselectivities of Claisen rearrangements of meta-substituted benzyl ketene acetals favour 1,2,3-trisubstituted products in preference to the less sterically congested 1,2,4-isomers due to favourable orbital interactions in the 1,2,3 transition state.

A new synthetic method for non-symmetric pillar[5]arenes with simple isolation and improved yield by Jiaming Ding; Jiafu Chen; Weipeng Mao; Junrou Huang; Da Ma (7894-7897).
The conventional method to synthesize non-symmetric pillar[n]arenes (PA[n]s) generally results in a low yield and requires laborious isolation. We developed a new synthetic method to prepare non-symmetric PA[5]s with various substitutions. Monomers were synthesized starting from commercially available chemicals. The desired products could be easily isolated with an improved yield.

N-Heterocyclic carbene palladium-catalyzed cascade annulation/alkynylation of 2-alkynylanilines with terminal alkynes by Jianxiao Li; Can Li; Lu Ouyang; Chunsheng Li; Wanqing Wu; Huanfeng Jiang (7898-7908).
A straightforward and highly effective N-heterocyclic carbene-palladium catalyzed cascade annulation/alkynylation of 2-alkynylanilines with terminal alkynes has been enabled to afford free (NH)-3-alkynylindole derivatives in moderate to good yields. This protocol features mild conditions, broad substrate scope, and high atom- and step-economy. Notably, the resultant 3-alkynylindoles could be conveniently transformed into a variety of functionalized indole scaffolds, thus illustrating their potential applications in synthetic and pharmaceutical chemistry.

Microwave-assisted synthesis of novel hetero[5]helicene-like molecules and coumarin derivatives by Wei Lin; Xiuxiu Hu; Shuai Song; Qi Cai; Yun Wang; Daqing Shi (7909-7916).
A concise and efficient approach to design and synthesize hetero[5]helicene-like molecules and coumarin derivatives is reported. Intriguingly, using the same catalyst (silica sulfuric acid), and a different solvent and reaction temperature, the reaction selectively afforded hetero[5]helicene-like molecules 3 or coumarin derivatives 4. Product 4 has a highly planar geometry, and product 3 can be regarded as hetero[5]helicene-like because of its helical conformation.

An ortho C-methylation/O-glycosylation motif on a hydroxy-coumarin scaffold, selectively installed by biocatalysis by Alexander Gutmann; Margaretha Schiller; Mandana Gruber-Khadjawi; Bernd Nidetzky (7917-7924).
Various bioactive natural products, like the aminocoumarin antibiotics novobiocin and coumermycin, exhibit an aromatic C-methyl group adjacent to a glycosylated phenolic hydroxyl group. Therefore, tailoring of basic phenolic scaffolds to contain the intricate C-methyl/O-glycosyl motif is of high interest for structural and functional diversification of natural products. We demonstrate site-selective 8-C-methylation and 7-O-β-d-glucosylation of 4,5,7-trihydroxy-3-phenyl-coumarin (1) by S-adenosyl-l-methionine dependent C-methyltransferase (from Streptomyces niveus) and uridine 5′-diphosphate glucose dependent glycosyltransferase from apple (Malus×domestica). Both enzymes were characterized and shown to react readily with underivatized 1. However, glucosylation of the ortho-hydroxyl group prevented C-methylation, probably by precluding an essential substrate activation through deprotonation of 7-OH. Therefore, dual modification was only feasible when C-methylation occurred strictly before O-glucosylation. The target product was synthesized in near quantitative yield (98% conversion) from 500 μM 1 and its structure was confirmed by NMR. Combination of C-methyltransferase and O-glycosyltransferase reactions for synthetic tailoring of a natural product through biocatalysis was demonstrated for the first time.

Deuteration and tautomeric reactivity of the 1-methyl functionality of free-base dipyrrins by Brandon R. Groves; T. Stanley Cameron; Alison Thompson (7925-7935).
Regioselective reactivity of the 1-methyl group of free-base dipyrrins is explored, including discussion of tautomerism to provide exocyclic alkenyl reactivity. Deuterium is installed so as to generate dipyrrins substituted with deuterated methyl groups. Furthermore, the 1-methyl group reacts to become involved in C–C bonds involving only sp3-hybridised carbon atoms. The isolation of an elusive framework featuring a dipyrrin substituted with a pyrrole in a non-vinylogous fashion is also reported. The use of asymmetric dipyrrins featuring an electron-withdrawing group on one of the pyrrolic units results in regioselective reaction of the alpha-methyl group distal to the electron-withdrawing group.

A fluorescent pH probe for acidic organelles in living cells by Jyun-Wei Chen; Chih-Ming Chen; Cheng-Chung Chang (7936-7943).
A water-soluble pH sensor, 2-(6-(4-aminostyryl)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N, N-dimethylethanamine (ADA), was synthesized based on the molecular design of photoinduced electron transfer (PET) and intramolecular charge transfer (ICT). The fluorescence emission response against a pH value is in the range 3–6, which is suitable for labelling intracellular pH-dependent microenvironments. After biological evolution, ADA is more than a pH biosensor because it is also an endocytosis pathway tracking biosensor that labels endosomes, late endosomes, and lysosome pH gradients. From this, the emissive aggregates of ADA and protonated-ADA in these organs were evaluated to explore how this probe stresses emission colour change to cause these unique cellular images.

Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives by Serena Massari; Jenny Desantis; Giulio Nannetti; Stefano Sabatini; Sara Tortorella; Laura Goracci; Violetta Cecchetti; Arianna Loregian; Oriana Tabarrini (7944-7955).
Two facile and efficient one-step procedures for the regioselective synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines have been developed, via reactions of 3,5-diamino-1,2,4-triazole with variously substituted 1-aryl-1,3-butanediones and 1-aryl-2-buten-1-ones, respectively. The excellent yield and/or regioselectivity shown by the reactions decreased when ethyl 5-amino-1,2,4-triazole-3-carboxylate was used. [1,2,4]Triazolo[1,5-a]pyrimidine being a privileged scaffold, the procedures herein reported may be useful for the preparation of biologically active compounds. In this study, the preparation of a set of compounds based on the [1,2,4]triazolo[1,5-a]pyrimidine scaffold led to the identification of compound 20 endowed with a very promising ability to inhibit influenza virus RNA polymerase PA–PB1 subunit heterodimerization.

Rational design and structure–activity relationship studies of quercetin–amino acid hybrids targeting the anti-apoptotic protein Bcl-xL by Tahsin F. Kellici; Maria V. Chatziathanasiadou; Min-Sung Lee; Nisar Sayyad; Elena G. Geromichalou; Eirinaios I. Vrettos; Antonis D. Tsiailanis; Seung-Wook Chi; George D. Geromichalos; Thomas Mavromoustakos; Andreas G. Tzakos (7956-7976).
Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein. IFD calculations determined their binding cavity while Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations provided an insight into the binding enthalpies of the analogues. The quercetin analogues were synthesized and their binding to Bcl-xL was verified with fluorescence spectroscopy. The binding affinity and the thermodynamic parameters between Bcl-xL and quercetin-glutamic acid were estimated through Isothermal Titration Calorimetry. 2D 1H–15N HSQC NMR chemical shift perturbation mapping was used to chart the binding site of the quercetin analogues in the Bcl-xL that overlapped with the predicted poses generated by both IFD and MD calculations. Furthermore, evaluation of the four conjugates against the prostate DU-145 and PC-3 cancer cell lines, revealed quercetin–glutamic acid and quercetin–alanine as the most potent conjugates bearing the higher cytostatic activity. This pinpoints that the chemical space of natural products can be tailored to exploit new hits for difficult tractable targets such as protein–protein interactions.

Correction: Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity by Fabien Stauffert; Jenny Serra-Vinardell; Marta Gómez-Grau; Helen Michelakakis; Irene Mavridou; Daniel Grinberg; Lluïsa Vilageliu; Josefina Casas; Anne Bodlenner; Antonio Delgado; Philippe Compain (7977-7977).
Correction for ‘Stereodivergent synthesis of right- and left-handed iminoxylitol heterodimers and monomers. Study of their impact on β-glucocerebrosidase activity’ by Fabien Stauffert et al., Org. Biomol. Chem., 2017, 15, 3681–3705.

Back cover (7979-7980).