Organic & Biomolecular Chemistry (v.15, #38)

Front cover (7981-7981).

Inside front cover (7982-7982).

Contents list (7983-7992).

Molecular simulations of peptide amphiphiles by Anjela Manandhar; Myungshim Kang; Kaushik Chakraborty; Phu K. Tang; Sharon M. Loverde (7993-8005).
This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles and drug-amphiphiles. The ability to predict the structure and stability of peptide self-assemblies from the molecular level up is vital to the field of nanobiotechnology. Computational methods such as molecular dynamics offer the opportunity to characterize intermolecular forces between peptide-amphiphiles that are critical to the self-assembly process. Furthermore, these computational methods provide the ability to computationally probe the structure of these supramolecular assemblies at the molecular level, which is a challenge experimentally. Herein, we briefly highlight progress in the areas of all-atomistic and coarse-grained simulation studies investigating the self-assembly process of short peptides and peptide amphiphiles. We also discuss recent all-atomistic and coarse-grained simulations of the self-assembly of a drug-amphiphile into elongated filaments. Next, we discuss how these computational methods can provide further insight into the pathway of cylindrical nanofiber formation and predict their biocompatibility by studying the interaction of these peptide-amphiphile nanostructures with model cell membranes.

Incorporation of [2H1]-(1R,2R)- and [2H1]-(1S,2R)-glycerols into the antibiotic nucleocidin in Streptomyces calvus by Xuan Feng; Nawaf Al Maharik; Axel Bartholomé; Jeffrey E. Janso; Usa Reilly; David O'Hagan (8006-8008).
Deuterium incorporations from [2H1]-(1R,2R) and [2H1]-(1S,2R) glycerols into the fluorine containing antibiotic nucleocidin, in Streptomyces calvus indicate that one deuterium atom is incorporated at the C-5′ site of nucleocidin from each of these isotopomers of glycerol. Two deuteriums become incorporated at C-5′ of nucleocidin after a feeding experiment with [2H5]-glycerol. These observations indicate that there is no obligate oxidation of the pro-R hydroxymethyl group of glycerol as it progresses through the pentose phosphate pathway and becomes incorporated into the fluorinated antibiotic.

Room-temperature Cu-catalyzed N-arylation of aliphatic amines in neat water by Deping Wang; Yanwen Zheng; Min Yang; Fuxing Zhang; Fangfang Mao; Jiangxi Yu; Xiaohong Xia (8009-8012).
A room-temperature and PTC-free copper-catalyzed N-arylation of aliphatic amines in neat water has been developed. Using a combination of CuI and 6,7-dihydroquinolin-8(5H)-one oxime as the catalyst and KOH as the base, a wide range of aliphatic amines are arylated with various aryl and heteroaryl halides to give the corresponding products in up to 95% yield.

Double 1,4-addition of (thio)salicylamides/thiosalicylic acids with propiolate derivatives: a direct, general synthesis of diverse heterocyclic scaffolds by Hui-Hong Wang; Tao Shi; Wei-Wei Gao; Hong-Hua Zhang; Yong-Qiang Wang; Jun-Fang Li; Yong-Sheng Hou; Jin-Hong Chen; Xue Peng; Zhen Wang (8013-8017).
A simple and practical ring-closure procedure to prepare a range of diverse heterocycles has been developed. In this transformation, a variety of substituted (thio)salicylamides and thiosalicylic acids undergo a double 1,4-addition reaction with propiolate derivatives in the presence of an inorganic base (K3PO4), as a result benzothiazinones, benzoxazinones and benzoxathiinones were prepared in good to excellent yields, respectively, even in gram scales. In addition, further transformation towards more complex structures and oxicam drug analogues has also been successfully carried out.

Development of a smart activity-based probe to detect subcellular activity of asparaginyl endopeptidase in living cells by Jong-Ah Hong; Na-Eun Choi; Yeo-Kyoung La; Ho Yeon Nam; Jiwon Seo; Jiyoun Lee (8018-8022).
We developed a smart activity-based probe that detects the activity of asparaginyl endopeptidase (AEP) in live cells to monitor the dynamics of enzyme regulation. The newly designed probe generated a turn-on fluorescence signal in response to the activity of AEP in living cells without compromising the labelling efficiency or selectivity. Our probe closely reflected the enzyme activity in its native state, detecting subcellular AEP activity in colon cancer cells and neuronal cells.

A versatile platform for adding functional properties to amyloid fibrils by Devon F. A. Fontaine; Valerie A. Ivancic; Michael B. Reardon; Noel D. Lazo; Charles E. Jakobsche (8023-8027).
Herein we report the design, synthesis, and testing of prototype members of a family of amyloid-binding molecular tools that can manipulate the fibrils by giving them various new functional properties. Potential applications include manipulating disease-relevant fibrils, developing novel functional nanomaterials, and studying the molecular details of fibril structures.

Thermoresponsive cyclodextrins with benzenesulfonamide showing tunable inhibition for carbonic anhydrase by Apan Qian; Huang Shi; Runlang Zhu; Jiatao Yan; Wen Li; Kun Liu; Afang Zhang (8028-8031).
Monodisperse thermoresponsive cyclodextrins appended with benzenesulfonamides were demonstrated to reversibly regulate the enzymatic activity of carbonic anhydrase, which was found to be dependent on both scaffold effect and thermoresponsiveness.

An enantioselective organocatalytic domino Michael-hemiacetalization reaction between alkylidene pyrazolones and cyclic ketones/pentanal has been revealed. The fused tetrahydropyranopyrazole products having three contiguous stereocentres were obtained with perfect diastereoselectivities and in moderate to good yields with good to high enantioselectivities. Also, few synthetic transformations of the product including the formation of a spiro derivative have been demonstrated.

Pnicogen bonding is a noncovalent interaction between the electrophilic region of a phosphorus atom and a Lewis base. Although this interaction can be comparable in strength to other noncovalent interactions, no systematic application in organic synthesis or catalysis is known so far. To identify the potential of this interaction for organocatalysis, we have now analysed different pnicogen-bond donors as catalysts for the activation of three different model reactions employing density functional theory. Our calculations suggest rate accelerations of several orders of magnitude for all cases indicating that synthetic applications should be feasible. Furthermore, our results indicate that pnicogen-bond donors can be comparable to halogen-bond-based catalysts in these reactions.

Supramolecular alleviation of cardiotoxicity of a small-molecule kinase inhibitor by Xue Yang; Qiaoxian Huang; David Bardelang; Chunming Wang; Simon M. Y. Lee; Ruibing Wang (8046-8053).
Small-molecule kinase inhibitors (SMKIs) have been widely used in the treatment of a variety of cancers due to their clinically demonstrated efficacy. However, the use of some SMKIs, such as sorafenib (SO), has been plagued by their cardiotoxicity that has been frequently observed in treated patients. Herein we report that the encapsulation of SO by a synthetic receptor cucurbit[7]uril (CB[7]) alleviated the inherent cardiotoxicity of SO, as demonstrated in an in vivo zebrafish model. Moreover, the anti-cancer activity of SO was well preserved, upon its encapsulation by CB[7], as demonstrated by both in vitro and in vivo cancer/angiogenesis models. This discovery may provide new insights into a novel supramolecular formulation of SMKIs for the management of their side-effects.

One-pot synthesis of 2,3-difunctionalized indoles via Rh(iii)-catalyzed carbenoid insertion C–H activation/cyclization by Honggui Lv; Jingjing Shi; Bo Wu; Yujuan Guo; Junjun Huang; Wei Yi (8054-8058).
Reported herein is the first Rh(iii)-catalyzed carbenoid insertion C–H activation/cyclization of N-arylureas and α-diazo β-keto esters. The redox-neutral reaction has the following features: good to excellent yields, broad substrate/functional group tolerance, exclusive regioselectivity, and no need for additional oxidants or additives, which render this methodology as a more efficient and versatile alternative to the existing methods for the synthesis of 2,3-difunctionalized indoles.

The blue cheese-making fungus Penicillium roqueforti produces isofumigaclavine A as the main ergot alkaloid. Recently, genome mining revealed the presence of two DNA loci bearing the genetic potential for its biosynthesis. In this study, a short-chain dehydrogenase/reductase (SDR) from one of the loci was proved to be responsible for the conversion of chanoclavine-I to its aldehyde. Furthermore, a putative gene coding for an enzyme with high homology to Old Yellow Enzymes (OYEs) involved in the ergot alkaloid biosynthesis was found outside the two clusters. Biochemical characterisation of this enzyme, named FgaOx3Pr3, showed that it can indeed catalyse the formation of festuclavine in the presence of a festuclavine synthase FgaFS, as had been observed for other OYEs in ergot alkaloid biosynthesis. Differing from other homologues, FgaOx3Pr3 does not convert chanoclavine-I aldehyde to its shunt products in the absence of FgaFS. Instead, it increases significantly the product yields of several SDRs for the conversion of chanoclavine-I to its aldehyde. Kinetic studies proved that overcoming the product inhibition is responsible for the observed enhancement. To the best of our knowledge, this is the first report on the bifunctionality of an OYE and its synergistic effect with SDRs.

In the presence of triethylamine, the addition reaction of substituted α-amino acid alkyl esters including ethyl hyperphenylalaninate, phenylalaninate, isoleucinate, and alaninate with dialkyl but-2-ynedioate afforded active β-enamino esters, which in turn reacted with aromatic aldehydes and malononitrile to give tetrahydroimidazo[1,2-a]pyridine derivatives in moderate yields. Under similar reaction conditions, the reaction of ethyl glycinate with dialkyl but-2-ynedioate resulted in a 1,3-dipolar azomethine ylide, which reacted further with in situ-generated arylidene malononitrile, alkyl cyanoacetate, and cyanoacetamide to give polysubstituted pyrrolidine derivatives in good yields.

Palladium-catalyzed oxidative coupling of arylboronic acid with isocyanide to form aromatic carboxylic acids by Zhen-Bang Chen; Kui Liu; Fang-Ling Zhang; Qing Yuan; Yong-Ming Zhu (8078-8083).
A valuable palladium-catalyzed oxidative coupling of aryl- and alkenyl borides with isocyanide for the synthesis of corresponding carboxylic acids has been developed. With wide substrate scopes and good functional group tolerance, this reaction offers corresponding carboxylic acids in moderate to excellent yields.

The FeCl3/ZnI2-catalyzed synthesis of angularly fused furans by intermolecular coupling between enols and alkynes has been developed in ambient air. The methodology is successfully applicable to 4-hydroxycoumarin, 4-hydroxyquinolinone and α-tetralone affording regioselective 2-aryl furans in good yields. The control experiments suggest the possibility of a radical reaction mechanism.

Near-infrared (NIR) fluorescent probes are advantageous over visible ones, for they can avoid the interference from the short-wavelength background emission in biological systems. However, there are a very limited number of NIR probes that can specifically label target proteins in living cells. In this work, a series of long-wavelength dyes (N-NIR, S-NIR, and K-NIR) analogous to the novel Changsha NIR family are synthesized conveniently through a new approach that is different from the previously reported one. These three dyes have similar conjugation structures but exhibit tunable photophysical properties. N-NIR and S-NIR have large extinction coefficients over 100 000, and high fluorescence quantum yields. Although NIR absorption and emission of K-NIR are inferior to the former two, it emits in a much longer wavelength region. And all the three dyes can easily pass through the cell membranes to obtain the high-resolution NIR fluorescence images. Furthermore, N-NIR is chosen as the NIR fluorophore to develop a protein-labeling reagent PYBG-D, since it demonstrates the highest fluorescence quantum yield of up to 0.4 (in methanol). PYBG-D is efficiently synthesized through Sonogashira coupling between bromo-substituted N-NIR and alkyne-substituted benzylguanine (PYBG). The conjugate PYBG-D proves to be a specific and efficient label for O6-alkylguanine-DNA alkyltransferase (SNAP-tag) that fused to target proteins in living cells, which contributes to high resolution NIR fluorescence images under a laser confocal microscope.

Visible light-induced C3-sulfonamidation of imidazopyridines with sulfamides by Yongyuan Gao; Shu Chen; Weiye Lu; Weijin Gu; Ping Liu; Peipei Sun (8102-8109).
A visible light-induced regioselective sulfonamidation of imidazo[1,2-a]pyridines was developed using sulfamides as the nitrogen sources and aqueous NaClO solution as the oxidant under mild conditions. With the imidazo[1,2-a]pyridines bearing various substituents, the reaction proceeded smoothly to furnish the C3-sulfonamidation products in moderate to good yields. The method was also suitable for the sulfonamidation of some other imidazoheterocycles.

On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives by Germain Homerin; Emmanuelle Lipka; Benoît Rigo; Amaury Farce; Joëlle Dubois; Alina Ghinet (8110-8118).
In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson–Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a–h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a–h), modulation of the position 3 (compounds 2–5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2–5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.

A gold-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes has been developed. This method provides a concise and straightforward route to functionalized indolizines through the construction of the pyridine ring of indolizines and also allows elaboration of its pyrrole moiety with or without functional groups. In addition, a wide variety of functional groups, such as aryl, alkenyl, alkynyl, pyridyl or thienyl groups, can be easily incorporated into the pyridine unit of the indolizine products under mild conditions. The utility of the indolizine products was demonstrated by their efficient transformations into various C3-functionalized indolizine derivatives.

Copper-catalyzed oxidative cross-coupling of α-aminocarbonyl compounds with primary amines toward 2-oxo-acetamidines by Chuang Chen; Menghua Zhu; Lihui Jiang; Zebing Zeng; Niannian Yi; Jiannan Xiang (8134-8139).
A general and mild method for the construction of a carbon–nitrogen bond via copper-catalyzed oxidative cross-coupling of amines with α-aminocarbonyl compounds was achieved. Amines, either aliphatic primary amines, aromatic primary amines or secondary amines can be used as the starting materials. When R2 was different from R3, two isomers would be observed. Therefore, this reaction system has a broad substrate scope and provides a facile pathway for the synthesis of 2-oxo-acetamidines.

Singlet oxygen-mediated one-pot chemoselective peptide–peptide ligation by Eirini Antonatou; Yentl Verleysen; Annemieke Madder (8140-8144).
We here describe a furan oxidation based site-specific chemical ligation approach using unprotected peptide segments. This approach involves two steps: after photooxidation of a furan-containing peptide, ligation is achieved by reaction of the unmasked keto–enal with C- or N-terminal α-nucleophilic moieties of the second peptide such as hydrazine or hydrazide to form a pyridazinium or pyrrolidinone linkage respectively.

Synthesis and thermal stabilities of oligonucleotides containing 2′-O,4′-C-methylene bridged nucleic acid with a phenoxazine base by Yuki Kishimoto; Akane Fujii; Osamu Nakagawa; Tetsuya Nagata; Takanori Yokota; Yoshiyuki Hari; Satoshi Obika (8145-8152).
We designed and synthesized a novel artificial 2′-O,4′-C-methylene bridged nucleic acid (2′,4′-BNA/LNA) with a phenoxazine nucleobase and named this compound BNAP. Oligodeoxynucleotide (ODN) containing BNAP showed higher binding affinities toward complementary DNA and RNA as compared to ODNs bearing 2′,4′-BNA/LNA with 5-methylcytosine or 2′-deoxyribonucleoside with phenoxazine. Thermodynamic analysis revealed that BNAP exhibits properties associated with the phenoxazine moiety in DNA/DNA duplexes and characteristics associated with the 2′,4′-BNA/LNA moiety in DNA/RNA duplexes.

Directed nucleophilic addition of phenoxides to cyclopropenes by Pavel Yamanushkin; Michael Lu-Diaz; Andrew Edwards; Nicolai A. Aksenov; Marina Rubina; Michael Rubin (8153-8165).
The alkali metal-templated addition of aryloxides across the double bond of non-conjugated cyclopropenes is described. High cis-selectivity is achieved through a directing effect of a strategically positioned carboxamide functionality.

The highly enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl–β-amido allyl ester substituted oxindoles in good yields of 41–75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl–α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl–β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94–98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56–63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl–α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.

Silyl-substituted aromatic compounds can participate as the electrophilic component in palladium-catalysed cross-couplings, and reactivity is enhanced by a neighbouring silyl-group. Products analogous to those obtained from C–H activation chemistry are accessible by this means with the additional benefit of regiochemistry defined by the site of silyl substitution. DFT studies described here show that the mechanism of C–Si cleavage is distinct from previously recognised mechanisms for C–H cleavage, with a cascade of silyl intermediates en route to a stable product. The amide directing-groups are involved only in the stabilisation of palladacyclic intermediates, and are never disposed to activate silicon directly. 5-Membered and 6-membered palladacycles are known to behave differently in coupling reactions and the calculations reveal underlying reasons in the cationic pathways studied here.

A study of synthetic approaches to 2-acyl DHA lysophosphatidic acid by Yoshinori Yamamoto; Toshimasa Itoh; Keiko Yamamoto (8186-8192).
Lysophosphatidic acid (LPA) is a chemical mediator with a very simple glycerophospholipid structure. 1-Acyl LPA and 2-acyl LPA are biosynthesized in vivo. Unlike 1-acyl LPA, the biological function of 2-acyl LPA has been hardly elucidated and even organic synthesis of 2-acyl LPA had not been established. We suppressed acyl migration by formation of a salt with a phosphate group in order to synthesize 2-acyl LPA condensed with docosahexaenoic acid.

A versatile two-step synthesis of C4- and C5-arylated 2′-deoxyribosylimidazoles was elaborated using enzymatic N-transglycosylation followed by microwave-assisted Pd-catalysed arylation reactions. We report herein the reaction conditions that permit managing regioselectivity (N3 versus N1-isomers) in the enzymatic glycosylation of 4-iodoimidazole using the nucleoside N-deoxyribosyltransferase from L. leichmannii. Regiocontrolled glycosylation was also observed among several other imidazole derivatives studied, providing simple access to isomers not readily accessible by chemical routes. Finally, a series of flexible nucleosides was obtained in one step from 4- or 5-iodo-imidazole nucleosides by the Suzuki–Miyaura cross-coupling reaction with (hetero)aryl-boronic acids in aqueous media. Moreover, this chemoenzymatic approach is compatible with a one-pot two-step process affording a straightforward access to a broad array of potential anticancer and antiviral drugs as well as new DNA building blocks.

RNA-directed off/on switch of RNase H activity using boronic ester formation by Maëva Reverte; Ivan Barvik; Jean-Jacques Vasseur; Michael Smietana (8204-8210).
RNase H is a non-specific endonuclease which degrades selectively the RNA strand in DNA/RNA duplexes. We demonstrate in the present study that 5′-boronic acid modified oligonucleotides hybridized to a RNA target sequence converts RNase H to an inactivated enzyme complex. The dynamic formation of a boronate ester upon addition of a diol moiety disrupts the enzyme-inhibitor complex and reactivates RNase H. Moreover, we show that reactivation of RNase H function can also be engineered through short RNA trimers inputs that fashion RNase H from a non-specific DNA-guided enzyme into an informational and programmable RNA-guided one. Examples of programmable RNA recognition and cleavage illustrate the potential of this new stimuli-responsive system.

Synthesis and photophysical properties of a bichromophoric system hosting a disaccharide spacer by T. Papalia; A. Barattucci; S. Campagna; F. Puntoriero; T. Salerno; P. Bonaccorsi (8211-8217).
The synthesis of an efficient energy donor–acceptor system is reported, together with its photophysical properties. The bichromophoric species has been conceived to show potentialities for biological applications since a biocompatible disaccharide spacer, constituted of d-galactose and d-glucose derivatives, was used in compound 12 to connect two BODIPY units with different absorption/emission properties. The luminescence spectrum in acetonitrile of 12 shows an intense fluorescence band with a maximum at about 770 nm that is almost identical to that of the lowest-energy BODIPY, regardless of the excitation wavelength used. The quantum yield is 0.2 with an excited state lifetime of 2.5 ns. Excitation and ultrafast transient absorption spectroscopy demonstrates that a very efficient energy transfer takes place in 12 from the highest-energy lying BODIPY subunit to the lowest-energy emissive BODIPY moiety, with a time constant of about 31 ps. Noteworthily, the emission of 12 falls in the near infrared window, suitable for potential biological applications.

Recent advances in the synthesis of analogues of phytohormones strigolactones with ring-closing metathesis as a key step by Chiara Lombardi; Emma Artuso; Eleonora Grandi; Marco Lolli; Francesca Spirakys; Emanuele Priola; Cristina Prandi (8218-8231).
In this paper, we synthesized and evaluated the biological activity of structural analogues of natural strigolactones in which the butenolide D-ring has been replaced with a γ-lactam. The key step to obtain the α,β-unsaturated-γ-lactam was an RCM on suitably substituted amides. Strigolactones (SLs) are plant hormones with various developmental functions. As soil signaling chemicals, they are required for establishing beneficial mycorrhizal plant/fungus symbiosis. Beside these auxinic roles, recently SLs have been successfully investigated as antitumoral agents. Peculiar to the SL perception system is the enzymatic activity of the hormone receptor. SARs data have shown that the presence of the butenolide D-ring is crucial to retain the biological activity. The substitution of the butenolide with a lactam might shed light on the mechanism of perception. In the following, a dedicated in silico study suggested the binding modes of the synthesized compounds to the receptor of SLs in plants.

Correction: Recent advances in the synthesis of analogues of phytohormones strigolactones with ring-closing metathesis as a key step by Chiara Lombardi; Emma Artuso; Eleonora Grandi; Marco Lolli; Francesca Spyrakis; Emanuele Priola; Cristina Prandi (8232-8232).
Correction for ‘Recent advances in the synthesis of analogues of phytohormones strigolactones with ring-closing metathesis as a key step’ by Chiara Lombardi, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c7ob01917c.

Back cover (8233-8234).