Cation-induced ring-opening and oxidation reaction of photoreluctant spirooxazine–quinolizinium conjugates

• Phil M. Pithan,
• Sören Steup and
• Heiko Ihmels

Beilstein J. Org. Chem. 2020, 16, 904–916, doi:10.3762/bjoc.16.82

• the quinolizinium ion to develop photoswitchable functional quinolizinium derivatives. With this goal in mind, we synthesized and investigated the spirooxazine–quinolizinium conjugates 3a and 3b. But much to our surprise, our studies revealed that these derivatives are among the rare examples of

• photoreluctant spirooxazine derivatives with regard to the electrocyclic ring opening, and they could not be employed as molecular photoswitches. At the same time, however, we discovered that the addition of Cu2+ or Fe3+ to the conjugates 3a and 3b, respectively, led to the fast and quantitative formation of

• indolinonaphthoxazoles. Herein, we present the synthesis of, and investigation on the conjugates 3a and 3b, as well as mechanistic studies on the metal ion-induced formation of the derivatives 4a and 4b, along with the pertinent spectroscopic data of the products. Results and Discussion Synthesis The spirooxazine

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

• Panagiotis S. Gritzapis,
• Panayiotis C. Varras,
• Nikolaos-Panagiotis Andreou,
• Katerina R. Katsani,
• Konstantinos Dafnopoulos,
• George Psomas,
• Zisis V. Peitsinis,
• Alexandros E. Koumbis and
• Konstantina C. Fylaktakidou

Beilstein J. Org. Chem. 2020, 16, 337–350, doi:10.3762/bjoc.16.33

• amidoxime, ethanone oxime and aldoxime (VI, VII, VIII, R1 = p-pyridyl, Figure 1) as DNA photosensitizers. Based on our previous experimental results with o-, m- and p-pyridine oximes as carriers of the carboxylic [9] and sulfonic [11] ester conjugates, we proclaimed p-substituted pyridine ring as the most

• appropriate oxime supporting scaffold for experimenting with our novel carbamate esters, because this ring exhibited a better profile compared to the other pyridine analogues [9][11]. In order to provide a structure–activity relationship study, a series of O-carbamoyl conjugates consisted of benzyl as well as

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• the electron donor effect of the methylene substituent decreases the thermodynamic stability of the cis form compared to that report by Hecht [13], protein conjugates of 1 would be highly stable in vivo over the course of a typical daily mouse behavioral experiment [15]. cis-MAHoCh has a significantly

• retention time on UPLC (Figure 3). LC–MS analysis revealed a molecular ion confirming the addition product 12. Under the conditions we used for this chemical reaction it was complete within a few minutes. It has been reported that maleimide–peptide conjugates undergo hydrolysis of the succinimide to give a

• physiological conditions. The broad success [22] of this strategy since 2004 [19] suggests that even though careful in silico modeling is a standard step in photoprobe development [22], this is always performed with unhydrolyzed conjugates. Perhaps for long-term use in vivo an additional modeling step involving

Photoreversible stretching of a BAPTA chelator marshalling Ca²⁺-binding in aqueous media

• Aurélien Ducrot,
• Arnaud Tron,
• Robin Bofinger,
• Ingrid Sanz Beguer,
• Jean-Luc Pozzo and
• Nathan D. McClenaghan

Beilstein J. Org. Chem. 2019, 15, 2801–2811, doi:10.3762/bjoc.15.273

• chelating groups would also have a significant effect. Some groups reported BAPTA-diarylethene and EDTA-spiropyran conjugates, while noting limitations for implementation in terms of fatigue, solubility and relatively small affinity changes [25][26]. We further highlight a structurally elegant design

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• ) or Ni(II) with N-propargylmaleimide via the CuAAC click reaction to afford fluorinated porphyrin–triazole–maleimide conjugates. New maleimide derivatives were isolated in reasonable yields and identified by UV–vis, 1H NMR, 19F NMR spectroscopy and mass-spectrometry. Keywords: chlorin; maleimide

• the maleimide group with its rich biological activity to the tetrapyrrole macrocycles with their unique photophysical properties may result in new conjugates with improved chemical, biological and anticancer characteristics [28]. Moreover, maleimide is a stable functionality that rapidly and

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• tetra-ortho-fluoroazobenzene–PNA conjugates have promising properties (fast reversible isomerization, exceptional thermal stability, high isomer conversions and sensitivity to visible-light irradiation) as reversible modulators to control oligonucleotide hybridization in biological contexts. Furthermore

• compatible with the standard TFA/m-cresol/H2O (90:5:5) acidolysis yielding the photoswitchable PNA conjugates. These and all further studied PNAs in this work (Table 2) were purified by reversed-phase (RP) HPLC and fully characterized. Analogous compounds lacking the photoswitch were used as controls. First

• synthesized longer PNA conjugates (6–11, 18 and 19) with flanking lysines, which improved the solubility of the probes. In addition, we compared our probes with the ones that contained the classical unmodified azobenzene moiety (Azo) (PNA 12–17). The lower stability of the unmodified cis-Azo forced us to

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• ] and was also found to be cytotoxic with localization to the endoplasmic reticulum [8]. The cytotoxicity of compound 2 prompted the preparation and evaluation of compound 2 conjugates with porphyrins [9] and steroids [10] for targeted uptake of compound 2 into cancer cells, and the conjugates showed

• these compounds for further work including synthetic modifications using azide–alkyne Huisgen cycloaddition. We previously showed the preparation of fluorescent trilobolide conjugates [8] that retained the activity of the parental compounds and proved to be useful for live-cell imaging. In this article

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

• Rosana Ribić,
• Ranko Stojković,
• Lidija Milković,
• Mariastefania Antica,
• Marko Cigler and
• Srđanka Tomić

Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174

• the adjuvant activity in experiments in vivo [20][21]. Two series of manno-conjugates were prepared: (i) derivatives with glycolyl linker and (ii) the ones with (R)-hydroxyisobutyryl linker which is present in the parent ManAdTP. The glycolic linker was introduced due to the fact that N-glycolyl

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• paraformaldehyde and benzyl isocyanide to form hybrid 11 in good yield. Similarly, the spirostanic lactone 12 was transformed into spirostanic acid 13 and amine 14, which were next ligated to alanine methyl ester and Boc-histidine leading to the amino acid–steroid conjugates 15 and 16, respectively. This approach

• Conjugation of steroids to carbohydrates and peptides The conjugation of steroids to other biomolecules such as carbohydrates and peptides represents a valuable strategy for providing new properties to the hydrophobic steroid skeleton. Naturally occurring steroid–sugar conjugates such as saponins have shown

• to possess physicochemical and biological features different from those of the two separate molecular entities [57][58]. Despite nature does not provide examples of steroid–peptide conjugates, chemists have produced such conjugates to be employed as protease-like artificial enzymes [59] as mimics of

Self-assembly behaviors of perylene- and naphthalene-crown macrocycle conjugates in aqueous medium

• Xin Shen,
• Bo Li,
• Tiezheng Pan,
• Jianfeng Wu,
• Yangxin Wang,
• Jie Shang,
• Yan Ge,
• Lin Jin and
• Zhenhui Qi

Beilstein J. Org. Chem. 2019, 15, 1203–1209, doi:10.3762/bjoc.15.117

• Materials & Engineering (IBME), Northwestern Polytechnical University, Xi’an, Shaanxi 710072, P. R. China 10.3762/bjoc.15.117 Abstract The synthesis of conjugates of perylene diimide (PDI) and naphthalene diimide (NDI) modified with two benzo-21-crown-7 ethers (B21C7) are herein described. Their self

• attempted to combine these two classical organic moieties and crown macrocycle together and reported the PDI- and NDI-B21C7 conjugates. Their self-assemblies behaviors in aqueous medium were thus probed. Results and Discussion The synthetic route toward compounds 1 and 2 is shown in Scheme 1. Initially, the

• × 10−4 M. Synthetic route of perylene- and naphthalene-crown macrocycle conjugates 1 and 2. Supporting Information Supporting Information File 388: Experimental and analytical data. Acknowledgements We gratefully acknowledge financial support from the Thousand Talents Program of China, Postdoctoral

A chemically contiguous hapten approach for a heroin–fentanyl vaccine

• Yoshihiro Natori,
• Candy S. Hwang,
• Lucy Lin,
• Lauren C. Smith,
• Bin Zhou and
• Kim D. Janda

Beilstein J. Org. Chem. 2019, 15, 1020–1031, doi:10.3762/bjoc.15.100

• of chemically contiguous drug–hapten conjugates, we envisioned generating a series of structurally diverse heroin–fentanyl haptens with a focus on linker placement and bond distance between each drug’s chemical connections in order to probe the effect of the drug-epitope structure on eliciting an

• least amount of glycerol had the highest number of hapten copies (i.e., 11.1 copies). Addition of 50% w/w glycerol reduced the hapten density by one-half (i.e., 5.2 copies). After dialysis, the solutions remained translucent, but the protein conjugates did not crash out of the solution. As a reference

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

Towards the preparation of synthetic outer membrane vesicle models with micromolar affinity to wheat germ agglutinin using a dialkyl thioglycoside

• Dimitri Fayolle,
• Nathalie Berthet,
• Bastien Doumeche,
• Olivier Renaudet,
• Peter Strazewski and
• Michele Fiore

Beilstein J. Org. Chem. 2019, 15, 937–946, doi:10.3762/bjoc.15.90

• present several advantages compared to natural and synthetic glycolipids, linked by a chemically and enzymatically non-stable acetal function. Owing to their straightforward access, and the stability of thioether conjugates, 1-thio-β--glucopyranose (1a, Figure 1), and 2-acetamido-2-deoxy-1-thio-β

Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• , mechanosynthesis of lipids by ball milling techniques has remained essentially unexplored. In this work, a multistep synthetic route to access mono- and diacylglycerol derivatives by mechanochemistry has been realized, including the synthesis of diacylglycerol-coumarin conjugates. Keywords: ball mill; coumarin

Polyaminoazide mixtures for the synthesis of pH-responsive calixarene nanosponges

• Antonella Di Vincenzo,
• Antonio Palumbo Piccionello,
• Alberto Spinella,
• Delia Chillura Martino,
• Marco Russo and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2019, 15, 633–641, doi:10.3762/bjoc.15.59

• area of the nanosponge–metal nanoparticles conjugates. Experimental Materials. All the reagents and solvents needed were used as purchased (Aldrich, Fluka) without further purification. The calixarene derivative Ca [39] and the non-commercial nitroaniline derivatives 7–10 [31][33] were prepared

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• biochemical processes in living cells and to elaborate the next generation of NR+ derivatives and conjugates with the view of developing novel drug and food supplement candidates. This review provides an overview of the synthetic approaches, the chemical properties, and the structural and functional

• 28% yield and was contaminated with Nam. The removal of acetyl groups from 4a gave NR+Cl− in 38% yield as a mixture of β- and α-anomers, with β/α ratio being equal to 3:2. The work of Migaud et al. [28] describes novel vitamin B3 conjugates, which were generated by glycosylation of nicotinate

• conjugates of NR+. Modifications which include protection of 2′- and 3′-hydroxy goups and reduction of the pyridinium core are used when direct modifications at the 5′-position are not possible due to the cleavage of the glycosidic bond under the required conditions, or are troublesome due to the low

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• are considerably higher in energy, at +6.4 and +15.2 kcal/mol, respectively. It should be noted that the acid/base conjugates of these states (APH+, TC and YI, respectively) were not calculated, as these structures would have different numbers of atoms and so the energies would not be directly

• to 1.15 Å. Even with that constraint the energies obtained are within 2 kcal/mol of those of their conjugates (Table 1), showing that N1′ protonation/deprotonation has only marginal impact on the relative energies of the cofactor states. In the AP state, His70 interacts with the cofactor through a

• the YI state, which seemingly benefits from the new hydrogen bond from the water molecule to the C2 carbanion. Finally, as with model B, the geometries for the YIH+, APH+ and TCH+ states could not be obtained, as geometry optimizations lead to their respective conjugates. However, constrained

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• differential for tumor cells. Members of one prominent novel class of targeted anticancer drugs that has been developed over the last years are antibody–drug conjugates (ADCs) [9][10][11]. Due to their high antibody-mediated target specificity, ADCs are designed for selective treatments of tumor cells with

• market. However, many other ADC development projects are in clinical trials [12][13]. More recently, peptide–drug conjugates (PDCs) have been recommended as targeted therapeutics [14][15]. While sharing the ADCs’ therapeutic concept of targeted and highly selective drug addressing to the diseased cells

• been identified as fast and efficiently internalizing GPCR in those cells upon agonist binding [29][30]. The NPY Y1 receptor subtype for these reasons is a very promising molecular target to be addressed by selective peptide–drug conjugates (PDCs), notably for cancer treatment or diagnosis. However

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• amino acid cysteine is also cumbersome and challenging. Recently, Low et al. reported synthesis of various targeted conjugates in which fluorescent tag [37] has been attached in a solution phase reaction. Also, they have reported the synthesis of ligand-conjugated peptides containing a radiotracer

• (Kd ≈ 10 nM) to deliver attached cargos to the interior of cells. These targeting ligands, DUPA and pteroate, have been exploited in the design and synthesis of our new ligand targeted tracer conjugates 13 and 17 (Figure 2) to target PSMA+ and FR+ diseased conditions. Analysis of the crystal structure

• − PC-3 cells (Figure 3). The negative cell line was used to prove the protein specificity of newly synthesized ligand targeted bioconjugates 13 and 17. In Figure 3 the confocal microscopic images depict the delivery of conjugates to cells via receptor-mediated endocytosis negating any possibility of

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• , Department of Infection, Immunity and Inflammation, University of Leicester, Maurice Shock Medical Sciences Building, University Road, Leicester, LE1 9HN, UK 10.3762/bjoc.14.242 Abstract Siderophore–antibiotic conjugates consist of an antibiotic covalently linked by a tether to a siderophore. Such

• conjugates can demonstrate enhanced uptake and internalisation to the bacterial cell resulting in significantly reduced MIC values and extended spectrum of activity. Phenothiazines are a class of small molecules that have been identified as a potential treatment for multidrug resistant tuberculosis and

• chelating groups of the siderophore. The synthesis is readily amenable to the preparation of analogues whereby the siderophore component of the conjugate can be modified. The route will be used to prepare a library of siderophore–phenothiazine conjugates for full biological evaluation of much needed new

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• and of the amide group to Phe338 in the CAS and between the nitrogen atom of the amide group to Tyr124 in the PAS were the key interactions of the synthesized 3-aminocoumarin-N-benzylpyridinium conjugates in the binding pocket of AChE. Conclusion A series of 3-amino-6,7-dimethoxycoumarins conjugated

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• -targeting by application of a GnRH analog as a carrier to deliver a covalently linked chemotherapeutic drug directly to the tumor cells. In this study our aim was (i) to analyze the effects of GnRH-drug conjugates on melanoma cell proliferation, adhesion and migration, (ii) to study the mechanisms of tumor

• cell responses, and (iii) to compare the activities of conjugates with the free drug. Results: In the tested conjugates, daunorubicin (Dau) was coupled to 8Lys of GnRH-III (GnRH-III(Dau=Aoa)) or its derivatives modified with 4Lys acylated with short-chain fatty acids (acetyl group in [4Lys(Ac)]-GnRH

• -III(Dau=Aoa) and butyryl group in [4Lys(Bu)]-GnRH-III(Dau=Aoa)). The uptake of conjugates by A2058 melanoma model cells proved to be time dependent. Impedance-based proliferation measurements with xCELLigence SP system showed that all conjugates elicited irreversible tumor growth inhibitory effects

Practical tetrafluoroethylene fragment installation through a coupling reaction of (1,1,2,2-tetrafluorobut-3-en-1-yl)zinc bromide with various electrophiles

• Ken Tamamoto,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 2375–2383, doi:10.3762/bjoc.14.213

• lead to a significant contribution as a first scalable CF2CF2 fragment installation method. To be further convinced of the importance of the present reaction, we carried out an additional transformation of the coupling adduct 4n to a CF2CF2-containing π-conjugates molecule, a fluorinated tolane

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• linkages that can be formed between native functional groups would be safe alternatives, and are known as natural conjugates such as nucleopeptides and nucleolipids [49]. We have been developing alkyl chain soluble support (ACSS)-assisted liquid-phase methods, specifically for peptide and oligonucleotide

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• dimethylformamide, has been shown to be influential in terms of efficacy and stereoselectivity [19]. Since its infancy, the Mitsunobu reaction has found applications in carbohydrate chemistry, as its broad scope and mild conditions are ideal for the formation of conjugates with sensitive natural products. Standard