Organic & Biomolecular Chemistry (v.13, #41)

Front cover (10253-10253).

Inside front cover (10254-10254).

Contents list (10255-10261).

Insights into the catalytic mechanism of synthetic glutathione peroxidase mimetics by Debasish Bhowmick; Govindasamy Mugesh (10262-10272).
Glutathione Peroxidase (GPx) is a key selenoenzyme that protects biomolecules from oxidative damage. Extensive research has been carried out to design and synthesize small organoselenium compounds as functional mimics of GPx. While the catalytic mechanism of the native enzyme itself is poorly understood, the synthetic mimics follow different catalytic pathways depending upon the structures and reactivities of various intermediates formed in the catalytic cycle. The steric as well as electronic environments around the selenium atom not only modulate the reactivity of these synthetic mimics towards peroxides and thiols, but also the catalytic mechanisms. The catalytic cycle of small GPx mimics is also dependent on the nature of peroxides and thiols used in the study. In this review, we discuss how the catalytic mechanism varies with the substituents attached to the selenium atom.

Results of density functional theory calculations on possible mechanisms for formation of the diterpenoid cyclooctatin are described. These results are consistent with the involvement of an unexpected 1,3-alkyl shift that interconverts two cyclopropylcarbinyl carbocations and interchanges the positions of two carbon atoms in an 8-membered ring. Predictions for future experiments to provide further support of this mechanism also are described.

Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin–lipid interactions by Jin Cui; Satoshi Kawatake; Yuichi Umegawa; Sébastien Lethu; Masaki Yamagami; Shigeru Matsuoka; Fuminori Sato; Nobuaki Matsumori; Michio Murata (10279-10284).
Phosphatidylglycerophosphate methyl ester (PGP-Me), a major constituent of the archaeal purple membrane, is essential for the proper proton-pump activity of bacteriorhodopsin (bR). We carried out the first synthesis of the bisphosphate head group of PGP-Me using H-phosphonate chemistry that led to the production of a simplified PGP-Me analogue with straight alkyl chains. To investigate the role of this head group in the structural and functional integrity of bR, the analogue was used to reconstitute bR into liposomes, in which bR retained the original trimeric structure and light-induced photocycle activity. Enhanced ordering of an alkyl chain of the 2H-labelled analogue was observed in 2H NMR spectra upon interaction with bR. These results together suggest that the bisphosphate moiety plays a role in the proper functioning of bR through the lipid–protein interaction.

Various 2,4,6-trisubstituted 1,3,5-triazines were smoothly formed via TBHP-mediated direct oxidative coupling of amidine and methylarenes. This tandem oxidation–imination–cyclization transformation exhibits a straightforward protocol to prepare 1,3,5-triazines from easily available starting materials and green oxidants under metal-free conditions.

Small molecules capable of eradicating non-replicating bacterial biofilms are of great importance to human health as conventional antibiotics are ineffective against these surface-attached bacterial communities. Here, we report the discovery of several halogenated quinolines (HQs) identified through a reductive amination reaction that demonstrated potent eradication of MRSA (HQ-6; MBEC = 125 μM), MRSE (HQ-3; MBEC = 3.0 μM) and VRE (HQ-4, HQ-5 and HQ-6; MBEC = 1.0 μM) biofilms. HQs were evaluated using the Calgary Biofilm Device (CBD) and demonstrated near equipotent killing activities against planktonic and biofilm cells based on MBC and MBEC values. When tested against red blood cells, these HQ analogues demonstrated low haemolytic activity (3 to 21% at 200 μM) thus we conclude that these HQ analogues do not operate primarily through the destruction of bacterial membranes, typical of other biofilm-eradicating agents (i.e., antimicrobial peptides). HQ antibacterial agents are potent biofilm-eradicating compounds and could lead to useful treatments for biofilm-associated bacterial infections.

A visible-light-promoted chloramination of olefins is reported. N-Chlorosulfonamides serve as both nitrogen and chlorine sources. These reactions provide a simple, efficient, regioselective, and atom-economical method for the preparation of vicinal haloamine derivatives under mild reaction conditions. A variety of olefins were tolerated, and chloramination products were obtained in good yields.

Radical 1,2-aryl migration in α,α-diaryl allylic alcohols toward β-silyl ketones by Haibo Peng; Jin-Tao Yu; Yan Jiang; Jiang Cheng (10299-10302).
A copper-catalyzed radical 1,2-aryl migration in α,α-diaryl allylic alcohols is developed, leading to β-silyl carbonyl compounds in moderate to good yields. The migration of aryls with lower aromaticity is favored. This procedure features the employment of silanes as commercially available materials.

Nicotinamide adenine dinucleotide (NAD) is a pivotal redox cofactor of primary metabolism. Its redox reactivity is based on the nicotinamide mononucleotide (NMN) moiety. We investigated whether NMN+ can engage in pairing interactions, when incorporated into an oligonucleotide. Here we describe the incorporation of NMN+ at the 3′-terminus of an oligodeoxynucleotide via a phosphoramidate coupling in solution. The stability of duplexes and triplexes with the NMN+-containing strand was measured in UV-melting curves. While the melting points of duplexes with different bases facing the nicotinamide were similar, triplex stabilities varied greatly between different base combinations, suggesting specific pairing. The most stable triplexes were found when a guanine and an adenine were facing the NMN+ residue. Their triplex melting points were higher than those of the corresponding triplexes with a thymidine residue at the same position. These results show that NMN+ residues can be recognized selectively in DNA helices and are thus compatible with the molecular recognition in nucleic acids.

Design, characterization and cellular uptake studies of fluorescence-labeled prototypic cathepsin inhibitors by Franziska Kohl; Janina Schmitz; Norbert Furtmann; Anna-Christina Schulz-Fincke; Matthias D. Mertens; Jim Küppers; Marcel Benkhoff; Edda Tobiasch; Ulrike Bartz; Jürgen Bajorath; Marit Stirnberg; Michael Gütschow (10310-10323).
Besides their extracellular activity crucial for several pathophysiological conditions, human cysteine cathepsins, in particular cathepsins K and S, represent important intracellular targets for drug development. In the present study, a prototypic dipeptide nitrile inhibitor structure was equipped with a coumarin moiety to function as a fluorescent reporter group. In a second inhibitor, a PEG linker was introduced between the dipeptide nitrile and the fluorophore. These tool compounds 6 and 7 were characterized by kinetic investigations as covalent reversible inhibitors of human cathepsins L, S, K and B. Probe 6 showed a pronounced inhibitory activity against cathepsins K and S, which was corroborated by modeling of inhibition modes. Probe 7 was highly potent (Ki = 93 nM) and selective for cathepsin S. To examine the ability of both probes to enter living cells, human embryonic kidney 293 cells were targeted. At a concentration of 10 μM, cellular uptake of probe 6 was demonstrated by fluorescence measurement after an incubation time of 30 min and 3 h, respectively. The probe's concentration in cell lysates was ascertained on the basis of the emission at 492 nm upon excitation at 450 nm, and the results were expressed as concentrations of probe 6 relative to the protein concentration originating from the lysate. After incubation of 10 μM of probe 6 for 3 h, the cellular uptake was confirmed by fluorescence microscopy. HPLC was used to assess the probes’ lipophilicity, and the obtained log D7.4 value of 2.65 for probe 6 was in agreement with the demonstrated cellular uptake.

Investigations into the binding of jadomycin DS to human topoisomerase IIβ by WaterLOGSY NMR spectroscopy by Camilo F. Martinez-Farina; Nicole McCormick; Andrew W. Robertson; Helen Clement; Alison Jee; Anna Ampaw; Nei-Li Chan; Ray T. Syvitski; David L. Jakeman (10324-10327).
The jadomycins are a family of secondary metabolites produced by S. venezuelae ISP5230. Specific jadomycins have been shown to possess a variety of anticancer, antifungal, and antibacterial properties, with different molecular mechanisms of action. Herein we demonstrate qualitative and quantitative direct binding between the validated anticancer target human topoisomerase IIβ and jadomycin DS using WaterLOGSY NMR spectroscopy. Additionally, we report for the first time, that jadomycin DS also binds a variety of other proteins, likely in a non-specific manner. Such interactions may rationalize the potential polypharmacology of jadomycin DS.

The α-fluorination of α- and β-C-ethanals of galactose using Jørgensen catalysts and NFSI was investigated. The crude reaction products were transformed to their primary alcohol or methylenated derivatives, which are versatile precursors to biologically interesting fluorinated glycomimetics. The α-C-glycoside substrate gave moderate to high yields of fluorinated α-C-glycosides with minor amounts of β-C-glycoside analogues. The reactions on the β-C-glycoside were lower yielding but gave exclusively fluorinated β-C-glycosides. For both α- and β-C-glycoside substrates (R) and (S) catalyst showed complementary stereoselectivity. The preparation of difluorinated materials required the use of racemic catalyst as enantiomerically pure catalyst gave intractable mixtures of products. These results are in line with the results for simple achiral aldehydes, and suggest that stereochemistry in the reactions of these chiral, highly substituted, carbohydrate-derived aldehydes are controlled primarily by the chirality in the catalyst.

Efficient Rh-catalyzed C–H borylation of arene derivatives under photochemical conditions by Charles Beromeo Bheeter; Abhishek Dutta Chowdhury; Rosa Adam; Ralf Jackstell; Matthias Beller (10336-10340).
Photocatalysis allows innovations in organic synthesis. Among the various catalytic reactions, CH-functionalizations offer valuable possibilities for the refinement of easily available building blocks. In this respect, catalytic borylation is of interest, too. So far, most of the catalytic borylation reactions are performed under thermal conditions at comparably high temperatures. Here, we describe a new synthetic route for efficient borylation reactions of arenes using a photocatalytic pathway. This novel approach allows the synthesis of a broad variety of borylated arenes and heteroarenes under mild conditions. Applying trans-[Rh(PMe3)2(CO)Cl] as an active photocatalyst and HBPin as an boron source, we achieved high TON. A catalytic cycle that relies on a Rh(i)–Rh(iii) interconversion is proposed.

An effective palladium-catalyzed enantioselective hydroesterification of alkenylphenols with phenyl formate as a CO source is described. A variety of optically active dihydrocoumarins can be obtained in generally high yields with up to 91% ee.

A new strategy for the simultaneous fluorogenic detection of two distinct enzyme activities namely hydrolase (amidase or esterase) and reductase is described. This innovative biosensing method is based on the powerful “covalent-assembly” principle that involves in situ synthesis of a fluorophore from a non-fluorescent caged precursor and through domino reactions triggered by the two analytes of interest. To establish this approach, penicillin G acylase (PGA) (or pig liver esterase (PLE)) and nitroreductase (NTR) were chosen as model enzymes, and original bis-O-protected 2,4-dihydroxycinnamonitrile derivatives acting as dual-reactive probes readily convertible to highly fluorescent 7-hydroxy-2-iminocoumarin scaffolds upon reacting with the two selected enzymes were synthesised. The two phenolic groups available within the core structure of these probes play a pivotal role in generating iminocoumarin scaffold through an intramolecular cyclisation reaction (hydroxyl group in C-2 position) and in enhancing its push–pull character (hydroxyl group in C-4 position). Their orthogonal and temporary protection with two different enzyme-labile masking groups is the cornerstone in the design of this novel class of fluorogenic “turn-on” probes. Their evaluation using fluorescence-based in vitro assays and HPLC-fluorescence/-MS analyses have enabled us both to demonstrate the claimed activation mechanism (in particular the specific order in which the two enzymes react with the probe) and to highlight the potential utility of these advanced chemical tools in multi-analyte sensing applications.

Irreversible electron attachment – a key to DNA damage by solvated electrons in aqueous solution by K. Westphal; J. Wiczk; J. Miloch; G. Kciuk; K. Bobrowski; J. Rak (10362-10369).
The TYT and TXT trimeric oligonucleotides, where X stands for a native nucleobase, T (thymine), C (cytosine), A (adenine), or G (guanine), and Y indicates a brominated analogue of the former, were irradiated with ionizing radiation generated by a 60Co source in aqueous solutions containing Tris as a hydroxyl radical scavenger. In the past, these oligomers were bombarded with low energy electrons under an ultra-high vacuum and significant damage to TXT trimers was observed. However, in aqueous solution, hydrated electrons do not produce serious damage to TXT trimers although the employed radiation dose exceeded many times the doses used in radiotherapy. Thus, our studies demonstrate unequivocally that hydrated electrons, which are the major form of electrons generated during radiotherapy, are a negligible factor in damage to native DNA. It was also demonstrated that all the studied brominated nucleobases have a potential to sensitize DNA under hypoxic conditions. Strand breaks, abasic sites and the products of hydroxyl radical attachment to nucleobases have been identified by HPLC and LC-MS methods. Although all the bromonucleobases lead to DNA damage under the experimental conditions of the present work, bromopyrimidines seem to be the radiosensitizers of choice since they lead to more strand breaks than bromopurines.

A four-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, 1,2-dibromoethane, and hydrazines under metal-free conditions is described, providing a novel and efficient approach to 2-arylsulfonyl hydrazones. This transformation proceeds smoothly via insertion of sulfur dioxide under mild conditions with good functional group tolerance.

Synthesis of (2-alkoxyphenyl)(9H-pyrido[3,4-b]indol-1-yl)methanone via Pd(OAc)2-catalyzed regioselective alkoxylation of aryl (β-carbolin-1-yl) methanones employing β-carboline directed ortho-C(sp2)–H activation of an aryl ring under oxidative conditions is described.

Pd catalyzed insertion of alkynes into cyclic diaryliodoniums: a direct access to multi-substituted phenanthrenes by Yongcheng Wu; Fuhai Wu; Daqian Zhu; Bingling Luo; Haiwen Wang; Yumin Hu; Shijun Wen; Peng Huang (10386-10391).
Cyclic diaryliodoniums remain unexplored compared to linear iodoniums. In our current work, internal alkynes were for the first time applied to react with cyclic iodoniums, catalyzed by Pd, resulting in a [4 + 2] benzannulation. Our work offers a new strategy to synthesize multi-substituted phenanthrene derivatives which are not easily accessed by conventional methods.

A single, appropriately designed, recognition event targets and transforms one of two reactive members of an exchanging pool of compounds through a recognition-mediated irreversible cycloaddition reaction, altering dramatically the final composition and kinetic behaviour of the dynamic library.

Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl isocyanide insertion by Xiang-Yuan Fan; Xiao Jiang; Ying Zhang; Zhen-Bang Chen; Yong-Ming Zhu (10402-10408).
An efficient one-pot palladium-catalyzed reaction for the synthesis of diazoles from readily available hydrazides and aryl halide via isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs diazoles in good to excellent yields with the advantages of wide functional group tolerance and operational simplicity.

Back cover (10409-10410).