Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• ratio. The latter was expected to be formed by halide counter ion exchange between CTAB and KI. Since the reaction occurred as expected, it was applied to the synthesis of amino acid conjugates. Acetyl groups of the (diacetoxyiodo)benzene were exchanged with N- and O-protected amino acids by slow

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• in compounds with increased therapeutic efficacy. The objective of the present study was to examine the cytotoxic effect of anticancer drug–GnRH-conjugates against two essential cardiovascular cell types, such as cardiomyocytes and endothelial cells. Sixteen different previously developed GnRH

• -conjugates containing doxorubicin, daunorubicin and methotrexate were investigated in this study. Their cytotoxicity was determined on primary human cardiac myocytes (HCM) and human umbilical vein endothelial cells (HUVEC) using the xCELLigence SP system, which measures impedance changes caused by adhering

• , at the highest concentrations tested. Doxorubicin-based conjugates (AN-152, GnRH-III(Dox-O-glut), GnRH-III(Dox-glut-GFLG) and GnRH-III(Dox=Aoa-GFLG) showed the same cytotoxic effect on cardiomyocytes. Among the daunorubicin-based conjugates, [4Lys(Ac)]-GnRH-III(Dau=Aoa), GnRH-III(Dau=Aoa-YRRL), {GnRH

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide–drug conjugates. Keywords: anticancer drugs; cell

• or basic character. During the last 25–30 years, many different CPPs have been described and used for manifold applications like the delivery of nucleic acids, proteins, peptides, nanoparticles, small organic drugs, and others [10]. CPP conjugates can be generated by covalent conjugation between

• sC18 is also able to enter cells directly to some extent, which is among others depending on the cell lines used [20]. For a further exploration and development of peptide–drug conjugates, peptide sequences that specifically accumulate at intracellular target sites are needed. CPPs have been already

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• analogues containing functional groups that would allow the conjugation of a homing device were developed [41][42][43][44][45][46]. Some of these functionalized analogues have been recently used for the preparation of antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) [46][47][48][49][50][51

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• ovarian carcinoma cells [43]. Khalaf et al. reported a new class of neutral, non-cationic minor groove binders derived from distamycin where the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. These conjugates exhibit

• reported other conjugates with two thiazoles directly linked via an amide bond, which retained activity to a lesser extent. Baraldi et al. designed and synthesized a novel conjugate 7 by combining naturally occurring antitumor agent distamycin A with the pyrrolo[2,1-c][1,4]benzodiazepine moiety (PBD

• fashion, they further reported a series of novel hybrids by tethering distamycin A with the antineoplastic agent uramustine via a flexible polymethylene chain of variable length (n = 1 to 6) in order to test their DNA binding affinity and cytotoxicity [57]. It has been observed that hybrid conjugates 8, 9

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide–drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors

• throughout this review. Among the most intriguing navigating delivery systems that can combine the transporting vehicle and the navigating/targeting moiety in a single module are the tumor-homing peptides [32]. These peptides are exploited to assemble the peptide–drug conjugates (PDCs) which are considered

• rationally installed taking into consideration the final derivative of the cytotoxic agent to retain the original cytotoxic activity. The sections below summarize the basic design principles of peptide–drug conjugates to selectively target the malignant cells. Selecting the proper tumor-targeting peptide to

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• Vienna, Austria 10.3762/bjoc.14.78 Abstract Cyclic NGR peptides as homing devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both

• CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys

• was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• synthesized and biochemically characterized in which 6Asp was replaced by D-Asp, D-Glu and D-Trp. In addition to the analysis of the in vitro cytostatic effect and cellular uptake, receptor binding studies with 125I-triptorelin as radiotracer and degradation of the GnRH-III conjugates in the presence of rat

• the ester bond resulting in a longer half-life of the conjugate during circulation. Nevertheless, the drug is released within the cancer cell by lysosomal enzymes, especially by cathepsin B, which leads to various Dau containing metabolites [26]. In case of GnRH-III–[8Lys(Dau=Aoa)] conjugates the

• smallest Dau metabolite obtained by lysosomal degradation is H-Lys(Dau=Aoa)-OH, which is able to bind to DNA resulting in a cytotoxic effect. A variety of oxime bond containing GnRH-III drug conjugates have been designed in our research group and their in vitro cytotoxic effects on hormone dependent human

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• , EC: 3.5.1) have been reported to hydrolyse glycinates and taurinates to the corresponding carboxylic acid. Recently, Pedrini et al. [33] have isolated and characterized a cholylglycine hydrolase from Xanthomonas maltophilia CBS 827.97: this enzyme completely hydrolyses glycine and taurine conjugates

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• nucleic acids (PNAs), a lipophilic triphenylphosphonium (TPP) cation was attached to the N-terminal extremity of a PNA through a biodegradable carbamate linker containing a disulfide bridge (Scheme 4B) [20]. It was shown that such PNA conjugates entered cells rapidly and efficiently. Furthermore, a 16-mer

• facilitate their uptake, a TAT-peptide delivery domain was conjugated to the siRNNs via A-SATE phosphotriester groups. Hence, a chimeric passenger strand containing four A-SATE phosphotriesters duplexed with an RNN guide strand was conjugated to the delivery domain TAT peptides. The resulting conjugates

• noncytotoxic fashion. Next, the authors prepared conjugates of the siRNNs via one A-SATE phosphotriester with a hepatocyte-specific tris-N-acetylgalactosamine targeting domain and demonstrated a stronger RNAi response in mouse liver (following subcutaneous or intravenous administration) than the same

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• C. Golgi, 19, I-20133, Milan, Italy Heidelberg Pharma Research GmbH, Schriesheimer Strasse 101, 68526, Ladenburg, Germany CNR, Istituto di Scienze e Tecnologie Molecolare (ITSM), Via C. Golgi, 19, 20133, Milan, Italy 10.3762/bjoc.14.29 Abstract RGD-α-amanitin and isoDGR-α-amanitin conjugates were

• synthesized by joining integrin ligands to α-amanitin via various linkers and spacers. The conjugates were evaluated for their ability to inhibit biotinylated vitronectin binding to the purified αVβ3 receptor, retaining good binding affinity, in the same nanomolar range as the free ligands. The

• antiproliferative activity of the conjugates was evaluated in three cell lines possessing different levels of αVβ3 integrin expression: human glioblastoma U87 (αVβ3+), human lung carcinoma A549 (αVβ3−) and breast adenocarcinoma MDA-MB-468 (αVβ3−). In the U87, in the MDA-MB-468, and partly in the A549 cancer cell

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• al. [94] reported the synthesis of aminobenzothiazole linked pyrazolo[1,5-a]pyrimidine conjugates (benzothiazolyl derivatives, 136). Methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine-5-carboxylates, obtained by the reactions of 5-aminopyrazole 16 with aryl-β-diketoesters 133 in ethanol, were hydrolyzed in

Synthesis and spectroscopic properties of β-meso directly linked porphyrin–corrole hybrid compounds

• Baris Temelli and
• Hilal Kalkan

Beilstein J. Org. Chem. 2018, 14, 187–193, doi:10.3762/bjoc.14.13

• obtaining multiporphyrin arrays [7][8][9] that could stabilize only metal ions in a bivalent state. To overcome this limitation, porphyrin conjugates with different chromophore groups such as fullerene [10][11][12], BODIPY [13][14][15], corrole [16][17][18][19][20][21][22][23], phthalocyanine [24][25][26

• characters, high fluorescence quantum yields and favorable electronic properties. Porphyrin–corrole conjugates have been successfully used as donor–acceptor systems in photoinduced charge separation processes. It was shown that derivatives of these conjugates could be potentially used in photovoltaic

• applications [21][22][23]. In order to achieve rapid energy and electron transfer between macrocycles, the short distance between subunits keeps an important place. Therefore, two important factors affect the physical and electronic properties of porphyrin–corrole conjugates: (i) type of linkers and (ii

Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• surface modification of AuNPs. In 2006, Brennan et al. demonstrated that enzyme–AuNP conjugates could be synthesized by CuAAC [47]. Azide-functionalized AuNPs were first synthesized by treating standard 14 nm Cit-AuNPs [28] with an a queous solution of an azide-containing thiol ligand (Scheme 7). An

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• structure of Ecm1 which forms a substrate binding cleft rather than a pocket [94]. Vinylbenzyl-modified cap analogues (bearing the modification at either the N7 or N2-position) provided a platform for inverse electron-demand Diels–Alder reactions with tetrazine conjugates and for photo-click reactions using

Pyrene–nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies

• Artur Jabłoński,
• Yannic Fritz,
• Hans-Achim Wagenknecht,
• Rafał Czerwieniec,
• Tytus Bernaś,
• Damian Trzybiński,
• Krzysztof Woźniak and
• Konrad Kowalski

Beilstein J. Org. Chem. 2017, 13, 2521–2534, doi:10.3762/bjoc.13.249

• Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki and Wigury 101, 02-089 Warszawa, Poland 10.3762/bjoc.13.249 Abstract Fluorescent pyrene–linker–nucleobase (nucleobase = thymine, adenine) conjugates with carbonyl and hydroxy functionalities in the linker were synthesized and

• compounds. The conjugates bearing a carbonyl function represent weak emitters as compared to compounds with a hydroxy function in the linker. The self-assembly properties of pyrene nucleobases were investigated in respect to their binding to single and double strand oligonucleotides in water and in buffer

• detecting markers [14], as fluorescent DNA probes [15], non-covalent binders to canonical oligonucleotide templates [16], and antiviral agents [17][18]. Notably, pyrene excimer formation in DNA template assemblies is much less efficient than in normal pyrene conjugates due to the helical twist between

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• ][91] or a peptide [92]. For example, TFEO-Pcs conjugated with peptides (15) have been reported [93]. A3B type TFEO-Pc was successfully condensed with peptides by palladium-catalyzed cross-coupling reactions in good yield (Scheme 5). These TFEO-Pc-peptide conjugates, which show a sharp Q band in the UV

• under Sonogashira cross-coupling conditions (Scheme 6). UV–vis absorption measurements suggested that the deoxyribonucleoside-linked TFEO-Pcs had a non-aggregation property, as expected. Unfortunately, it was also found that these conjugates gradually decomposed under light irradiation, so their

• application as an anticancer agent was discontinued. After that TFEO-ZnPc/cyclodextrin conjugates 18 were reported under similar conditions (Scheme 7) [100]. That study revealed that cyclodextrin-linked TFEO-Pcs have a non-aggregation property and sufficient water solubility, similar to the

Superstructures with cyclodextrins: Chemistry and applications IV

• Gerhard Wenz

Beilstein J. Org. Chem. 2017, 13, 2157–2159, doi:10.3762/bjoc.13.215

• insulin and lysozyme were also conjugated to the guest adamantane. The complexation of these conjugates by pegylated β-CD gives rise to superstructures which provide slow release and maintain full biological activity [21]. Significant progress was also achieved in the field of CD rotaxanes. A [3]-rotaxane

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• phosphodiester linkage upon ammonolytical deprotection. In other words, the ODNs were used as PEG-conjugates in biological studies. In addition, a bifunctionalized PEG, bearing the acid labile DMTrO group at one end and a base labile Fmoc-NH functionality at the other end, has been used as a soluble support to

• obtain oligonucleotide–PEG–peptide conjugates [55][56]. The Fmoc protecting group was first removed and the peptide was assembled on the exposed amino function. Since the peptide moiety did not contain acid labile side chain protections, the oligonucleotide sequence could then be assembled by the

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

• Ludmila Škorpilová,
• Silvie Rimpelová,
• Michal Jurášek,
• Miloš Buděšínský,
• Jana Lokajová,
• Roman Effenberg,
• Petr Slepička,
• Tomáš Ruml,
• Eva Kmoníčková,
• Pavel B. Drašar and
• Zdeněk Wimmer

Beilstein J. Org. Chem. 2017, 13, 1316–1324, doi:10.3762/bjoc.13.128

• theranostic applications. Keywords: BODIPY conjugates; cancer targeting; drug delivery; liposomes; natural compounds; sesquiterpene lactone trilobolide; Introduction Targeted (smart) drug delivery is a method for specific delivering of an active compound preferentially to some cells or tissues in the human

• class, which causes cell death via depleting intracellular Ca2+ ion stores by the irreversible inhibition of sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA) already at nanomolar concentrations [27][28][29][30]. In our recent study, we reported the localization of fluorescent Tb-BODIPY conjugates in the

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• recognition with the elucidation of glycosyl hydrolases mechanism by X-ray crystallography, but the scope of applications in glycobiology is much broader: it encompasses the range of glycan containing (macro)-molecules and their conjugates. The present article reviews the application of synchrotron radiation

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• carbohydrate conjugates in which the heterocyclic triazolyl ring serves as a shackle for joining the carbohydrate building blocks. Further, these carbohydrate conjugates decorated with appropriate coupling partner can be paired through ring closing metathesis (RCM) reaction. Carrying out the metathesis

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• -antibiotic conjugates, were prepared and resulted able to overcome antibiotic resistance of microbial biofilms, since CA NPs render streptomycin more accessible to biofilms, thereby more available to interact with biofilm bacteria [89]. Similarly, a novel recyclable E.coli-specific killing GAuNP

Cyclodextrins tethered with oligolactides – green synthesis and structural assessment

• Cristian Peptu,
• Mihaela Balan-Porcarasu,
• Alena Šišková,
• Ľudovít Škultéty and
• Jaroslav Mosnáček

Beilstein J. Org. Chem. 2017, 13, 779–792, doi:10.3762/bjoc.13.77

• not asses their products whether these were CD-VL, CD-LA or CD-VL/LA covalent conjugates [19][20]. The results presented by the Harada group generally evaluated the CD-oligoester samples by matrix-assisted laser desorption ionization mass spectrometry (MALDI–MS) and nuclear magnetic resonance (NMR

• The properties of cyclodextrin-oligoester covalent conjugates, situated at the border of low and high molecular weight compounds can be influenced by both the carbohydrate and the oligoester components. The properties of such materials like solubility, miscibility with other materials, inclusion

• spectroscopy. Liquid chromatography and tandem MS fragmentation studies [21][22][23] are also important additions in deeper structural characterization of CD-oligoester conjugates. The L-LA was reacted with α-, β- and γ-CD (Scheme 1) in bulk at 110 °C in order to ensure a good dispersion of reactants. The

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

• Nikolay V. Lukashev,
• Gennadii A. Grabovyi,
• Dmitry A. Erzunov,
• Alexey V. Kazantsev,
• Gennadij V. Latyshev,
• Alexei D. Averin and
• Irina P. Beletskaya.

Beilstein J. Org. Chem. 2017, 13, 564–570, doi:10.3762/bjoc.13.55

• transport of anions through lipid membranes [19][20][21][22]. Some of similar pincer compounds can be used as receptors for organic molecules; e.g., polyamino derivatives based on cholane skeleton can form complexes with amino acids [23] and pincer-like conjugates of deoxycholic acid and aminopyrene can