Organic & Biomolecular Chemistry (v.11, #14)

Front cover (2215-2215).

Inside front cover (2216-2216).

Contents list (2217-2223).

Bioconjugation on cube-octameric silsesquioxanes by Sebastian Fabritz; Sebastian Hörner; Olga Avrutina; Harald Kolmar (2224-2236).
Small, compact, and highly symmetric cube-octameric silsesquioxanes have recently attracted increased attention as scaffolds for tailor-made bioconjugates. The expanded arsenal of effective conjugation methods (CuAAC, TEC, oxime ligation) allows one to decorate these nanoparticles bearing up to eight addressable organic substituents, with a wide range of biorelevant ligands, among them carbohydrates, peptides, miniproteins, reporter molecules, and rare-earth chelates. Low toxicity of COSS-based molecules combined with solubility in aqueous systems and half-life sufficient for in vivo studies make these structures attractive targets for a number of applications, among them drug delivery, tumor diagnostics and therapy.

Synthesis of unsymmetrical carboxyphthalocyanines by palladium-catalyzed hydroxycarbonylation of iodo-substituted precursors by Íñigo Aguirre de Carcer García; Altug Mert Sevim; Andrés de la Escosura; Tomás Torres (2237-2240).
Phthalocyanines (Pcs) containing a carboxylic acid functionality directly bound to the macrocycle have been synthesized, in one step and in good yields, from iodo-substituted Pc precursors. This methodology represents a convenient alternative to the commonly used method based on two consecutive oxidations of hydroxymethyl Pcs.

In vitro evolution of a Friedel–Crafts deoxyribozyme by Utpal Mohan; Ritwik Burai; Brian R. McNaughton (2241-2244).
We report the in vitro selection of a single-stranded 72-nucleotide DNA enzyme (deoxyribozyme) that catalyzes a Friedel–Crafts reaction between an indole and acyl imidazole in good yield and in aqueous solvent. Appreciable Friedel–Crafts product requires addition of copper nitrate and the deoxyribozyme. We observe deoxyribozyme-mediated bond formation for both in cis and in trans Friedel–Crafts reactions.

Synthesis of green and blue fluorescent ladder-type conjugated imidazolium compounds by Koji Takagi; Yohei Ito; Kazuma Kusafuka; Masanori Sakaida (2245-2248).
The synthetic route to ladder-type conjugated imidazolium compounds consisting of Suzuki coupling, chlorination, and intramolecular cyclization reactions was developed. The optical properties of materials and theoretical calculations were investigated to demonstrate that methylene- and ethylene-bridged imidazolium compounds show green and blue fluorescence, respectively. The coordination ability of the counter anion had an influence on the solubility and fluorescence quantum yield of the compounds.

The rhodium-catalyzed intramolecular direct arylation of imidazole and benzimidazole derivatives via double C–H bond activation is described. This approach provides new access to a wide range of imidazo and benzimidazo[2,1-a]isoquinoline derivatives in moderate to high yields. This reaction provides an alternative method to the known Pd-catalyzed intramolecular oxidative cross-coupling reactions.

A naked-eye chemosensor for fluoride ions: a selective easy-to-prepare test paper by Xue Yong; Minjian Su; Wen Wang; Yichen Yan; Jinqing Qu; Ruiyuan Liu (2254-2257).
A new naked-eye chromogenic chemosensor based on 2-thiohydantoin shows high selectivity for fluoride ions and is used to develop a test paper for detection of fluoride ions in the solid state.

Cube-octameric silsesquioxane-mediated cargo peptide delivery into living cancer cells by Sebastian Hörner; Sebastian Fabritz; Henry D. Herce; Olga Avrutina; Christian Dietz; Robert W. Stark; M. Cristina Cardoso; Harald Kolmar (2258-2265).
Cube octameric silsesquioxanes (COSS) are among the smallest nanoparticles known to date with a diameter of only 0.7 nm. We describe a COSS-based delivery system which allows for the drug targeting in human cells. It comprises a siloxane core with seven pendant aminopropyl groups and a fluorescently labeled peptidic ligand attached to one cage corner via a reversible disulfide bond to ensure its intracellular release. Bimodal amplitude-modulated atomic force microscopy (AFM) experiments revealed the formation of dendritic COSS structures by a self-assembly of single particles on negatively charged surfaces. Nuclear targeting was demonstrated in HeLa cells by selective binding of released p21Cip1/Waf1-derived cargo peptide to PCNA, a protein involved in DNA replication and repair.

An easily available N-heterocyclic carbene–palladium(ii)–1-methylimidazole complex 1 showed efficient catalytic activity in the Suzuki–Miyaura coupling of benzylic chlorides with arylboronic acids or potassium phenyltrifluoroborate in neat water under mild conditions, providing an alternative method for the synthesis of diarylmethane derivatives, which widely exist in molecules with pharmaceutical activities and are also frequently found as subunits in supramolecules. Under the optimal conditions, all reactions performed well to give the desired products in moderate to almost quantitative yields in an environmentally benign medium within 12 h, extending their applications toward potentially industrial processes.

Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment by Sreejith P. Shankar; Monika Jagodzinska; Luciana Malpezzi; Paolo Lazzari; Ilaria Manca; Iain R. Greig; Monica Sani; Matteo Zanda (2273-2287).
Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure–activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins’ potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC50 displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues.

Synthetic and mechanistic insight into nosylation of glycine residues by Nicolai Stuhr-Hansen; Theis Ivan Sølling; Kristian Strømgaard (2288-2293).
The Fukuyama–Mitsunobu alkylation procedure is widely used to introduce alkyl substituents to amino groups in general and N-alkylation of peptides in particular. Here we have investigated the procedure in detail for N-alkylation of peptides with N-terminal glycine residues, based on the observation that standard conditions lead to substantial bis-nosylation of the glycine amino group. A systematic evaluation of this observation was carried out and it was demonstrated that for peptides with alanine, β-alanine or γ-aminobutyric acid (GABA) as N-terminal residues mono-nosylation was observed under the same conditions. Moreover, bis-nosylation was independent of the type of resin, neighboring amino acid and nature of the peptide. Calculations suggest that the reason for the bis-nosylation is the fact that the deprotonated mono-nosyl species is particularly stable in the case of the terminal Gly residue because the N residue can become closer to the SO2 unit. Finally, the mono-nosylated N-terminal glycine could be obtained by careful optimization of the procedure, adding only one equivalent of 2-nitrobenzenesulfonyl chloride.

A study on the substituent effects of norbornadiene derivatives in iridium-catalyzed asymmetric [2 + 2] cycloaddition reactions by Jun Hu; Qingjing Yang; Lu Yu; Jianbin Xu; Shanshan Liu; Chao Huang; Lin Wang; Yongyun Zhou; Baomin Fan (2294-2301).
Employing a series of norbornadiene derivatives as substrates, the effects of various substituents on the Ir-catalyzed asymmetric [2 + 2] cycloaddition reactions with arylacetylenes were studied. It was found that the atom forming the short bridge chain had a great effect on the enantioselectivity of the reaction. Heteroatoms, such as oxygen and nitrogen, always resulted in excellent enantioselectivity. However, carbon atoms could decrease the enantioselective control ability of the catalyst over the reaction. The groups on the unreacted carbon–carbon double bond were found to have but a little effect on the reaction. Based on the results of the experiments, a mechanism was also hypothesized for the reaction.

Specific nucleophile–electrophile interactions in nucleophilic aromatic substitutions by Rodrigo Ormazábal-Toledo; Renato Contreras; Ricardo A. Tapia; Paola R. Campodónico (2302-2309).
We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (SNAr) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile–electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes SNAr reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

Specific recognition of cytosine by hypoxanthine in pyrrolidinyl peptide nucleic acid by Chotima Vilaivan; Wimonmas Srinarang; Nattawut Yotapan; Woraluk Mansawat; Chalothorn Boonlua; Junji Kawakami; Yoshie Yamaguchi; Yuko Tanaka; Tirayut Vilaivan (2310-2317).
Hypoxanthine is an unnatural base that can potentially pair with all natural nucleobases. While hypoxanthine in DNA exhibits marginal preference for pairing with cytosine (C), little is known about its pairing behavior in other DNA analogues. In this study, we synthesized a hypoxanthine-containing monomer and incorporated it into pyrrolidinyl peptide nucleic acid with α/β-peptide backbone derived from d-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid (acpcPNA). DNA binding studies clearly revealed that hypoxanthine in acpcPNA behaves like G-analogue because it can specifically form a stable base pair with dC in DNA. The ability to replace G by hypoxanthine without affecting the base pairing properties of acpcPNA can solve a number of problems associated with G-rich acpcPNA including difficult synthesis, formation of secondary structures and fluorescence quenching.

A unique Rh(ii) and Ru(ii) catalyzed C–H oxygenation of aryl ketones and other arenes has been developed for the facile synthesis of diverse functionalized phenols. The reaction demonstrates excellent reactivity, regio- and chemoselectivity, good functional group compatibility and high yields. The practicality of this method has been proved by gram-scale synthesis of a few different 2-acylphenols. Its utility has been well exemplified in further applications in heterocycle synthesis and direct modifications of drug Fenofibrate.

Synthesis and applications of 2,4-disubstituted thiazole derivatives as small molecule modulators of cellular development by Garr-Layy Zhou; Daniel M. Tams; Todd B. Marder; Roy Valentine; Andrew Whiting; Stefan A. Przyborski (2323-2334).
Understanding how the structure of molecules relates to their function and biological activity is essential in the development of new analogues with targeted activity. This is especially relevant in mediating developmental processes in mammalian cells and the regulation of stem cell differentiation. In this study, thiazole-containing small molecules were synthesised and investigated for their ability to induce the differentiation of human pluripotent stem cells and their derivatives. Analyses of cell morphology, cell viability, expression of cell surface markers and ability to induce cell differentiation and regulate neurite formation identified the analogue with the longest and most bulky hydrophobic side chain as possessing comparable or enhanced activity to all-trans-retinoic acid (ATRA). Interestingly, a shorter, less bulky, known thiazole compound reported to be isoform selective for the retinoic acid receptor β2 (RARβ2) agonist did not mediate differentiation under the conditions tested; however, activity could be restored by adjusting the structure to a longer, more bulky molecule. These data provide further insight into the complexity of compound design in terms of developing small molecules with specific biological activities to control the development and differentiation of mammalian cells.

Regioselective C2-arylation of imidazo[4,5-b]pyridines by Jonathan Macdonald; Victoria Oldfield; Vassilios Bavetsias; Julian Blagg (2335-2347).
We show that N3-MEM-protected imidazo[4,5-b]pyridines undergo efficient C2-functionalisation via direct C–H arylation. Twenty-two substituted imidazo[4,5-b]pyridines are prepared and iterative, selective elaboration of functionalised imidazo[4,5-b]pyridines gives 2,7- and 2,6-disubstituted derivatives in good yields from common intermediates. Mechanistic observations are consistent with a concerted-metallation-deprotonation mechanism facilitated by coordination of copper(i)iodide to the imidazo[4,5-b]pyridine.

Electron densities of bexarotene and disila-bexarotene from invariom application: a comparative study by Peter Luger; Manuela Weber; Christian Hübschle; Reinhold Tacke (2348-2354).
By the application of the invariom formalism, which provides aspherical atomic scattering factors, the electron densities of the RXR-selective retinoid agonists bexarotene (1a) and disila-bexarotene (1b) were derived from their known low resolution (d = 0.76 Å) crystal structures. The density distributions allowed us to make a comparison of the electronic properties of these pharmacologically relevant compounds. Differences were found to be restricted to relatively small regions in the terminal six-membered rings of the tetrahydronaphthalene and tetrahydrodisilanaphthalene fragments. In total, the replacement of two carbon atoms in 1a by silicon atoms (→1b) does neither influence the electronic structures nor the pharmacological properties (RXR receptor activation) significantly. It should be noted that the almost completely software supported invariom formalism can yield electronic information for biologically interacting systems with moderate effort. This offers interesting possibilities for drug research, in that steric and electronic information can be combined for the analysis of intermolecular recognition and interaction on an atomic scale. This approach is also valuable for the design and development of silicon-containing drugs using the carbon/silicon switch strategy.

Six novel di-substituted phenanthroline derivatives 5a–7a and 3b–5b have been prepared, and their binding interactions with human telomeric (h-telo) and promoter (c-kit2 and c-myc) G-quadruplex DNAs were investigated. All the compounds are potent stabilisers of the G-quadruplex structures and compounds 3b, 4b, and 5b exhibit high G-quadruplex DNA selectivity over duplex DNA. The binding affinities of these compounds to G-quadruplex DNA are higher than to duplex DNA. CD spectra show that the compound can induce the formation of an anti-parallel structure of the h-telo G-quadruplex. Each h-telo quadruplex binds two compound molecules by the end-stacking mode. Six new compounds are able to inhibit significantly the telomerase activity at low μM concentration.

Fluoride as an inducible DNA cross-linking agent for new antitumor prodrug by Jun Wu; Rong Huang; Tianlu Wang; Xi Zhao; Wanyi Zhang; Xiaocheng Weng; Tian Tian; Xiang Zhou (2365-2369).
Two new small compounds, which undergo fluoride-mediated self rearrangement, produce active DNA alkylating agent nitrogen mustard leading to DNA damage and finally cell death, providing potential antitumor prodrugs.

Microwave-assisted synthesis of difficult sequence-containing peptides using the isopeptide method by Waleed M. Hussein; Tzu-Yu Liu; Istvan Toth; Mariusz Skwarczynski (2370-2376).
Microwave-assisted Fmoc solid phase peptide synthesis (SPPS) was applied in combination with the isopeptide strategy to establish a new method for the rapid synthesis of difficult sequence-containing peptide. A model peptide (8QSer) was produced in one day using the method developed, in contrast with two weeks using the isopeptide method. Both methods produced the desired peptide in high yield and purity, while classical SPPS did not result in the desired product.

Inside back cover (2377-2378).