Organic & Biomolecular Chemistry (v.12, #5)

Front cover (711-711).

Inside front cover (712-712).

Contents list (713-718).

Alkoxyamines: a new family of pro-drugs against cancer. Concept for theranostics by Gérard Audran; Paul Brémond; Jean-Michel Franconi; Sylvain R. A. Marque; Philippe Massot; Philippe Mellet; Elodie Parzy; Eric Thiaudière (719-723).
Development of anti-cancerous theranostic agents is a vivid field. This article describes a theranostic approach that relies on the triggering of cancer cell death by generation of alkyl radicals at the right place and at the right time using the presence of active proteases in the tumour environment. Alkoxyamines (R1R2NOR3) are labile molecules that homolyze into nitroxides (R1R2NO˙) and reactive alkyl radicals (R3˙). They are used as a source of active alkyl radicals for curing and nitroxides for monitoring by Overhauser-enhanced magnetic resonance imaging (OMRI). Herein, the requirements needed for applying alkoxyamines are described: (i) highly selective activation of the alkoxyamine by specific proteases; (ii) fast homolysis of the alkoxyamine C–ON bond at physiological temperature; (iii) activation of cell death processes through an increase of the local oxidative stress or potential re-activation of the immune system due to short-lived alkyl radicals; and (iv) imaging of the tumor and the drug release by sensing the nitroxide by OMRI.

Chiral Brønsted acid-catalyzed enantioselective addition of indoles to ketimines by Taichi Kano; Ryosuke Takechi; Ryohei Kobayashi; Keiji Maruoka (724-727).
A highly enantioselective addition of indoles to a readily available ketimine was found to be catalyzed by a chiral phosphoric acid. This organocatalytic process represents a rare example of an addition reaction to a non-aromatic ketimine.

Synthesis of substituted indenones and indanones by a Suzuki–Miyaura coupling/acid-promoted cyclisation sequence by Alexey N. Butkevich; Beatrice Ranieri; Lieven Meerpoel; Ian Stansfield; Patrick Angibaud; Andrei Corbu; Janine Cossy (728-731).
A one-pot Suzuki–Miyaura cross-coupling/acid-catalyzed cyclisation leading to indenones and indanones in modest to good yields is reported.

New facile enantio- and diastereo-selective syntheses of (−)-triptonide and (−)-triptolide by Hongrui Zhang; Haifeng Li; Jijun Xue; Rui Chen; Ying Li; Yu Tang; Chunxin Li (732-736).
A novel formal asymmetric synthesis of (−)-triptonide and (−)-triptolide, featuring a new alternative access to their known key intermediate 4, has been achieved through two synthetic routes in 9 steps with 13.6% total yield and 10 steps with 18.5% overall yield, respectively. This synthesis is scalable and hence has high potential for application to further synthetic elaboration and biologic investigation on such natural products.

Gold-catalyzed annulations of allenes with N-hydroxyanilines to form indole derivatives with benzaldehyde as a promoter by Rahul Kisan Kawade; Po-Han Huang; Somnath Narayan Karad; Rai-Shung Liu (737-740).
Gold-catalyzed syntheses of 2,3-disubstituted indole derivatives from N-hydroxyanilines and allenes are described; these reactions require benzaldehyde as an additive to generate nitrones in situ. Our control experiments indicate that nitrones and water were indispensable in the reactions whereas N-hydroxyanilines alone were inactive nucleophiles. This synthetic method is compatible with allenes and N-hydroxyanilines with a reasonable range, further highlighting its synthetic utility.

A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction of 2-(2-propynyl)aniline or 2-(2-propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3, and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity, compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods. A mechanism has been proposed to explain the product formation.

Catechols are components of many metal-chelating compounds, including siderophores that are naturally occurring iron(iii) chelators excreted by microorganisms. Catechol derivatives are poorly soluble in organic media and the synthesis of catechol-containing molecules requires the use of protected catechol precursors with improved organic solubility. We therefore developed 2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester. This activated ester reacts with an amine functionalized scaffold to generate chelators in which the catechol functions are protected in the form of diphenyl-benzodioxole moieties. The catechol can subsequently be deprotected, at the end of the synthesis, with trifluoroacetic acid (TFA). This strategy was applied to the synthesis of two catechol compounds functionalized with a terminal propargyl extension. These two compounds were shown to promote iron uptake in Escherichia coli and Pseudomonas aeruginosa. These two compounds are suitable for use as vectors in antibiotic Trojan horse approaches, as they could be conjugated with azide-functionalized antibiotics using the Huisgen dipolar 1,3-cycloaddition.

Cross-coupling/annulations of quinazolones with alkynes for access to fused polycyclic heteroarenes under mild conditions by Hui Lu; Qin Yang; Yirong Zhou; Yanqin Guo; Zhihong Deng; Qiuping Ding; Yiyuan Peng (758-764).
Ruthenium-catalyzed regioselective oxidative cross-coupling/annulations of quinazolones with alkynes were successfully developed for direct access to fused polycyclic heteroarenes. The transformation proceeded well with a broad substrate scope under mild conditions to achieve moderate to high yields.

Dimerization of a heat shock protein 90 inhibitor enhances inhibitory activity by Hendra Wahyudi; Yao Wang; Shelli R. McAlpine (765-773).
Heat shock protein 90 (hsp90) accounts for 1–2% of the total proteins in normal cells and it functions as a dimer. Hsp90 behaves as a molecular chaperone that folds, assembles, and stabilizes client proteins. We have developed a novel hsp90 inhibitor, and herein we describe the synthesis and biological activity of the dimerized variant of this inhibitor. Tethering a monomer inhibitor together produced a dimerized compound that more effectively inhibits hsp90 over the monomer.

Formation of a pseudo-β-hairpin motif utilizing the Ant–Pro reverse turn: consequences of stereochemical reordering by Roshna V. Nair; Amol S. Kotmale; Snehal A. Dhokale; Rupesh L. Gawade; Vedavadi G. Puranik; Pattuparambil R. Rajamohanan; Gangadhar J. Sanjayan (774-782).
Herein, we report a special case of pseudo-β-hairpin formation by tetrapetide sequences featuring a two-membered Ant–Pro dipeptide motif (Ant = anthranilic acid and Pro = proline) at the loop region. These folded structures uniquely feature the presence of C9- and C17-H-bonding patterns at reverse turn and interstrand regions, respectively. Their hairpin nucleation and folding propensities have been expounded using solution and solid state studies of distinct stereochemically altered sequences.

Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands by Mark E. Ashford; Vu H. Nguyen; Ivan Greguric; Tien Q. Pham; Paul A. Keller; Andrew Katsifis (783-794).
5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ12 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7–845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4–133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88–15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies.

CuI-catalyzed cycloisomerization of propargyl amides by Ali Alhalib; Wesley J. Moran (795-800).
The synthesis of substituted dihydrooxazoles by the CuI-catalyzed cycloisomerization of terminal propargyl amides is reported. The reaction has been shown to have good substrate scope and experiments to delineate the mechanism have been performed. Substrates containing a benzylic methylene were oxidized to the ketone under the reaction conditions.

Design, synthesis and evaluation of novel tacrine–rhein hybrids as multifunctional agents for the treatment of Alzheimer's disease by Su-Yi Li; Neng Jiang; Sai-Sai Xie; Kelvin D. G. Wang; Xiao-Bing Wang; Ling-Yi Kong (801-814).
A series of tacrine–rhein hybrid compounds have been designed and synthesized as novel multifunctional potent ChE inhibitors. Most of the compounds inhibited ChEs in the nanomolar range in vitro effectively. Compound 10b was one of the most potent inhibitors and was 5-fold more active than tacrine toward AChE, and it also showed a moderate BuChE inhibition with an IC50 value of 200 nM. Kinetic and molecular modeling studies of 10b also indicated that it was a mixed-type inhibitor binding simultaneously to the active and peripheral sites of AChE. In inhibition of the AChE-induced Aβ aggregation assay, compound 10b (70.2% at 100 μM) showed the greatest inhibitory activity. In addition, 10b showed metal-chelating property and low hepatotoxicity. These results suggested that 10b might be an excellent multifunctional agent for AD treatment.

Giant amino acids designed on the polysaccharide scaffold and their protein-like structural interconversion by Shun-ichi Tamaru; Daisuke Tokunaga; Kaori Hori; Sayaka Matsuda; Seiji Shinkai (815-822).
Amphoteric β-1,3-glucans possessing both amino groups and carboxylic acid groups on the C6 positions of glucose units were designed and synthesized from naturally produced curdlan. The amphoteric polysaccharides showed the isoelectric point and the pH responsive interconversion between the original triple helix and single-stranded random structures. Since the pH dependences are comparable to the typical properties of proteins, the polysaccharides can be considered as a new class of giant amino acids. Utilizing the pH responsiveness, pH-controlled catch-and-release has been realized for cationic peptides or anionic DNA. We believe that the amphoteric polysaccharide can act as a new potential polymer to construct stimuli-responsive smart materials on the basis of the polysaccharide scaffold.

Fluorescent macrocyclic probes with pendant functional groups as markers of acidic organelles within live cells by Prashant D. Wadhavane; M. Ángeles Izquierdo; Dennis Lutters; M. Isabel Burguete; María J. Marín; David A. Russell; Francisco Galindo; Santiago V. Luis (823-831).
A new family of acidity sensitive fluorescent macrocycles has been synthesized and fully characterized. Their photophysical properties including emission quantum yield and fluorescence lifetime have been determined. The acid–base properties of the new molecules can be tuned by the incorporation of pendant functional groups. The nature of such functional groups (carboxylic acid or ester) influences dramatically the pKa of the probes, two compounds of which exhibit low values. Preliminary intracellular studies using confocal microscopy together with emission spectra of the probes from the cellular environment have shown that the synthesized fluorescent macrocycles mark the acidic organelles of RAW 264.7 macrophage cells.

DABCO catalyzed the cross-Rauhut–Currier/transesterification reaction of α-cyano-α,β-unsaturated ketones and aryl acrylates was discovered. The reaction rate law was determined by an integral method under pseudo-first-order reaction conditions, which assisted in proposing the mechanism of cross-Rauhut–Currier reaction promoted by Brønsted acid and establishing the rate-determining step.

A single thionoglycine (glycine thioamide, –HNCH2C(S)–) residue inserted into a peptide foldamer provides both a pair of germinal protons for use as a 1H NMR stereochemical probe and a chromophore giving rise to a well defined Cotton effect in CD. Comparison of the response of these two features to a local helically chiral environment validates them as independent methods for quantifying the conformational screw-sense preference of a helical oligomer, in this case a peptide made of repeated Aib units. The sign of the Cotton effect provides a measure of the sign of the screw-sense preference, while both the chemical shift separation of the anisochronous signals of the glycine CH2 group and the magnitude of the Cotton effect give an estimate of the helicity excess of the oligomer. The thionoglycine unit is readily introduced synthetically by a thionation of a BocGlyAibOMe dipeptide.

The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer–template (FM–T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with trimethylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2.8) of 2 MIPs imprinted using TMS as the FM. The TMS–1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS–2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS–2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the π-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to π–π stacking interactions between 2 and TMS. These findings are consistent with the deviation from the ‘normal’ molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level of interference from other MIP synthesis components. The effect on PFS–1 interaction by MeOH was significantly lower and thus this system was not adversely affected.

Back cover (855-856).