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

• reported on the identification of a novel daunorubicin–GnRH-III conjugate (GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning

• after 10 min). Additional flow cytometry studies demonstrated that the cellular uptake of the bioconjugate was inhibited in the presence of the competitive ligand triptorelin indicating a receptor-mediated pathway. For comparative purpose, six novel daunorubicin–GnRH-III bioconjugates have been

• 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

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

• discussed vide infra in a separate section. The intracellular concentration of GSH ranges from 1 mM to 10 mM, which is 10–100 times higher than its extracellular concentration. Consequently, ON prodrugs should be stable outside the cell and, after cellular uptake, would be converted into the native ONs by

• for the use of 2’-O-RSSM-modified RNAs as prodrugs of siRNAs. Modifications at the extremities Disulfide bonds are attractive in designing drug-delivery systems. Indeed, lipophilic moieties may be attached to ONs to enhance cellular uptake. In particular, a cleavable disulfide linker has been used at

• vitro by nitroreductases as well as in tumor cell extract by cellular reductases (Scheme 5A) [25]. Furthermore, such nitrofuryl and nitrothienyl modifications improved nuclease resistance and cellular uptake of ONs in proportion to the number of lipophilic groups. In another study, a series of ONs with

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

• is responsible for the transcription of DNA to mRNA [1][2]. Despite this strong inhibitory activity, α-amanitin exhibits only a micromolar cytotoxicity and low cellular uptake in most mammalian cells, due to its strong polarity and poor membrane permeability [2]. One notable exception are human

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• into PNA, these PhpC derivatives exhibited a bright blue fluorescence with large fluorescence quantum yield (0.5–0.6), which can be useful for monitoring the cellular uptake and distribution of PNA [192]. In addition, the fluorescence was responsive to the base pairing, where up to 60% quenching was

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

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

• been used for eIF4E inhibition in vitro [80], the pro-drug 4Ei-1 bearing an N7-benzyl moiety was shown to be a potent inhibitor of cap-dependent translation in zebrafish [81]. Poor cellular uptake of cap analogues could be circumvented by coupling to an adenovirus-like particle, resulting in inhibition

Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

• Marco Russo,
• Daniele La Corte,
• Annalisa Pisciotta,
• Serena Riela,
• Rosa Alduina and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2751–2763, doi:10.3762/bjoc.13.271

• applications in biological systems, such as vectors for simultaneous drug and gene cellular uptake or alternatively for the protection of macromolecules. In particular, we exploited polarimetry to test their interaction with some model p-nitroaniline derivatives, chosen as probe guests. The data obtained

• , in term of both their pH-dependent overall charge and their conformational freedom. Third, the interactions of AmCDs with pDNA, studied by means of EMSA and transformation of E. coli Ca-competent cells assays, revealed a very strong binding, which ultimately hampers the desired cellular uptake. As a

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

• immunosorbent assay (ELISA), the selectivity and sensitivity of the binding were demonstrated to be dependent on the sugar nature and on the NP morphology. The cellular uptake experiments on HeLa, HepG2 and MDA-MB-231 cells showed in fact an higher clathrin-mediated internalization for rod-shaped AuNPs in

• fundamental issue for the efficacy of these nanomaterials [68]. The use of stealth coatings is an effective strategy to decrease or inhibit the non-specific interaction with plasma proteins (the so called “protein corona”), that can modify GAuNP biological identity, affecting aggregation, and cellular uptake

Synthesis of multi-lactose-appended β-cyclodextrin and its cholesterol-lowering effects in Niemann–Pick type C disease-like HepG2 cells

• Keiichi Motoyama,
• Rena Nishiyama,
• Yuki Maeda,
• Taishi Higashi,
• Yoichi Ishitsuka,
• Yuki Kondo,
• Tetsumi Irie,
• Takumi Era and
• Hidetoshi Arima

Beilstein J. Org. Chem. 2017, 13, 10–18, doi:10.3762/bjoc.13.2

• (DSL5.6) can enter ASGPR-expressing cells, we examined the intracellular distribution of tetramethylrhodamine isothiocyanate (TRITC)-multi-Lac-β-CD (DSL5.6) in NPC-like HepG2 cells (ASGPR positive cells) Figure 5. The cellular uptake of TRITC-multi-Lac-β-CD (DSL5.6) was observed in NPC-like HepG2 cells 24

• -CD and TRITC-HP-β-CD in NPC-like HepG2 cells were observed to be lower than that of TRITC-multi-Lac-β-CD (DSL5.6) (Figure 5B). In summary, these results indicate that multi-Lac-β-CD (DSL5.6) was distributed to the endolysosomes after cellular uptake by the NPC-like HepG2 cells. Effects of multi-Lac-β

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• inhibitors [19] or doxorubicin [20]. For the elucidation of the mechanisms involved in the efficacy of these promising nanomedicines, the precise knowledge regarding the cellular uptake, the intracellular localization and the determination of the subcellular interactions and trafficking is crucial. To

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• reflect several effects such as target interaction, cellular uptake and potential resistance mechanisms of the microorganism. MIC values are therefore widely used, also in studies on muraymycin analogues (e.g., [22][76][77][78]) and have been the basis of many structure–activity relationship studies (see

• with MIC values of 2 to 16 μg/mL, Enterococci with 16 μg/mL and higher to some Gram-negative bacteria (8 μg/mL). Against an E. coli mutant with increased membrane permeability, an MIC value below 0.03 μg/mL was obtained, suggesting that inhibition is a matter of cellular uptake of the compound. In vivo

• a semisynthetic approach for modifications of muraymycin C1 as starting point of their SAR studies (Figure 7) [86]. In accordance with the results reported by McDonald et al., their work was based on the assumption that the cellular uptake required for MraY inhibition is mainly dependent on fatty

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• -HexNAc [19], and 4,6-difluoro-D-GalNAc [19] were reported to exhibit antiproliferative properties against L1210 leukemia cells in micromolar concentrations (IC50 24–43 μM). It was found that O-deacetylated amino sugars were often inactive due to low lipophilicity and poor cellular uptake [19]. Compound 5

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• biological activity is connected with a prohibited cellular uptake. Despite our model cannot tell anything about the bioavailability, metabolic half-life or side effects, due to our computations, compound 1 would have a lower affinity than linezolid even if it arrives at the ribosomal target. Though 1

Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

• Keiichi Motoyama,
• Yumi Hirai,
• Rena Nishiyama,
• Yuki Maeda,
• Taishi Higashi,
• Yoichi Ishitsuka,
• Yuki Kondo,
• Tetsumi Irie,
• Takumi Era and
• Hidetoshi Arima

Beilstein J. Org. Chem. 2015, 11, 2079–2086, doi:10.3762/bjoc.11.224

• exert the pharmacological effects in vivo, since neither HP-β-CyD nor HP-γ-CyD enters cells effectively due to their hydrophilicity and high molecular weight. Receptor-mediated endocytosis is an attractive approach to enhance the cellular uptake of drugs in target cells. It enables not only high drug

• cholesterol trafficking and has the potential to induce NPC disease phenotype [16]. No significant cytotoxicity of Lac-β-CyD was observed in U18666A-treated HepG2 cells at 1 mM for 24 h. The following studies were performed under the experimental conditions. Cellular uptake of TRITC-Lac-β-CyD To reveal

• whether Lac-β-CyD can associate with ASGPR-expressing cells, we examined the cellular uptake of tetramethylrhodamine isothiocyanate (TRITC)-labeled Lac-β-CyD after treatment for 24 h in U18666A-treated HepG2 and NPC-like ASGPR-expressing cells, by a flow cytometric analysis (Figure 4). As a result, TRITC

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• a third component fluorescent dyes [10] were coupled to the polymers simultaneously with the bioactive and the cell-penetrating peptides in order to enable the monitoring of cellular uptake and intracellular distribution of the peptide–polymer conjugate. Until now, various polymer carriers have been

Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection

• Fatemeh Sheikhi Mehrabadi,
• Hanxiang Zeng,
• Mark Johnson,
• Cathleen Schlesener,
• Zhibin Guan and
• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 763–772, doi:10.3762/bjoc.11.86

• , arginine (Arg) and histidine (His). To investigate the effects from introducing Arg and His to dPG, the resulting polyplexes of amino acid functionalized dPG-NH2s (AAdPGs)/siRNA were evaluated regarding cytotoxicity, transfection efficiency, and cellular uptake. Among AAdPGs, an optimal vector with (1:3

• more are being developed [1]. Although a direct delivery of “naked” siRNA or chemically modified oligonucleotides [2] has been studied, delivery vectors are typically required for efficient siRNA delivery in vivo due to unmodified siRNA’s low stability towards endogenous enzymes, poor cellular uptake

• improve the cellular uptake [28]. Additionally, the histidine groups can facilitate tackling the endosomal release problem by improving the polyplexes’s buffering capacity [18]. Moreover, arginine and histidine groups can form intermolecular hydrogen bonds with cell surface phosphate groups. These

Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin

• Hale Ünal,
• Naile Öztürk and
• Erem Bilensoy

Beilstein J. Org. Chem. 2015, 11, 204–212, doi:10.3762/bjoc.11.22

• reason, an amphiphilic cyclodextrin (CD) derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with

• nanocapsules were then coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes and penetration through intestinal mucosa for absorption of CPT and reaching the circulation. Nanocapsules were characterized for their in vitro properties followed by cell

• attributed to the surface charge of the coating material chitosan. CS coated cationic NCs exhibited a stronger affinity for the negatively charged cell membrane [44]. CS can increase the chance of cellular uptake of nanoparticles by improving the residence time at the cellular surface due to the

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• their high polarity represents a significant hurdle for cellular uptake and leads to problematic pharmcokinetics. Furthermore, they are prone to nuclease-mediated degradation. As a consequence, it is of utmost importance to modify oligonucleotide structures using chemical or enzymatic methods in order

Conjugates of methylated cyclodextrin derivatives and hydroxyethyl starch (HES): Synthesis, cytotoxicity and inclusion of anaesthetic actives

• Lisa Markenstein,
• Antje Appelt-Menzel,
• Marco Metzger and
• Gerhard Wenz

Beilstein J. Org. Chem. 2014, 10, 3087–3096, doi:10.3762/bjoc.10.325

• was already discussed by Szejli as a very promising candidate for parenteral drug delivery [17], but it was placed back because of its high toxicity [5][18][19]. Therefore our aim was to conjugate DIMEB for the first time to a polymeric backbone, which should hinder cellular uptake. CD polymers are

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• that binding to DNA induces a little distortion in the double helix (covalent adducts with DNA) [86]. The increased activity was attributed to improved cellular uptake and consequent inhibition of the cellular life cycle, whereby inhibition was additionally correlated to more expedient binding to

• cellular uptake (Figure 11), upon which red colour of 19 accumulated in cell nuclei – intriguingly after only 2 hours fluorescence colour changed to yellow (Figure 11, right) and the dye distributed over the cytoplasm pointing out to the metabolic modification of the compound. The new, easily accessible

Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs

• Fabrizio Chiodo,
• Marco Marradi,
• Javier Calvo,
• Eloisa Yuste and
• Soledad Penadés

Beilstein J. Org. Chem. 2014, 10, 1339–1346, doi:10.3762/bjoc.10.136

• the improvement of the solubility in water and biological media of the drugs and the improvement of cellular uptake due to the presence of carbohydrates on the GNPs. In addition a local increase of the drug concentration on the gold surface could also improve their antiviral activity. We reasoned that

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• derivatives 1a,b of the A- and B-series, respectively (Figure 1) [7]. This significant change in potency might be owed to increased lipophilicity and thus to improved cellular uptake, as muraymycins inhibit the transmembrane protein MraY (translocase I), an enzyme involved in peptidoglycan formation with its

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• the cellular uptake of modified biosynthetic intermediates. Processing of these intermediates, sometimes called mutasynthons, can provide complex secondary metabolites specifically modified as planned by choice of the synthetic modification incorporated into the mutasynthon [5][6][7]. In earlier work

A peptidic hydrogel that may behave as a “Trojan Horse”

• Nicola Castellucci,
• Giorgio Sartor,
• Natalia Calonghi,
• Carola Parolin,
• Giuseppe Falini and
• Claudia Tomasini

Beilstein J. Org. Chem. 2013, 9, 417–424, doi:10.3762/bjoc.9.44

• carry drug molecules into the cell. For this purpose, we used the gelator A (Figure 1), derived from natural proteinogenic amino acids (Thr, Phe) and a fatty acid (azelaic acid). Compound A was prepared from Boc-L-Phe-D-Oxd-OBn and azelaic acid, as previously reported [23]. To check the cellular uptake

• as gelator, doped by a small amount of the dansyl-containing compounds B, C and D. These all readily form fluorescent hydrogels, which may be used to evaluate the cellular uptake of A. Before evaluating the cellular uptake of the hydrogels, the structure of 1 (hydrogel), and its corresponding xerogel

• with small amounts of dansyl-containing compounds, needed to show the cellular uptake into IGROV-1 cells by confocal laser scanning microscopy. These gels are readily internalized by cells and are biologically inactive. In contrast, the hydrogel 6 formed only by B and a water/ethanol mixture is

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• derivatives of biomacromolecules that have to be soluble in hydrophilic environments to be taken up in vivo or in cell culture. Common solubilizers that enhance the cellular uptake are polyamines and other polycationic moieties such as particular peptoids. Recently, polycationic polyamines have been shown to

• coupling sequence resulted in the peptoids, which were further modified with rhodamine B (Rho-CO2H) as an easily accessible and versatile fluorescent tag. Rhodamine B was coupled to the N-terminus in order to provide a label for future biological applications, such as the study of the cellular uptake. For

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• .8.233 Abstract Phallotoxins inhibit the dynamics of microfilaments in cells and lead to apoptosis. Due to poor cellular uptake these effects cannot be studied in live cells, even at millimolar toxin concentrations, nor can phalloidin be used for the elimination of tumor cells. Uptake is greatly enhanced

• , into live cells. Keywords: amatoxins; cellular uptake; endocytosis; peptides; phalloidin; phallotoxins; Introduction Phallotoxins and amatoxins, the two families of toxic cyclopeptides produced by the green death cap Amanita phalloides, have been the subject of intense biochemical research for

• cells Tetramethylrhodaminyl-phalloidin (Figure 6a) has been used to visualize actin fibers in fixed cells for 30 years. Here we show that the rhodamine residue also strongly enhanced cellular uptake, making this phalloidin derivative a tool for cell biology. With an IC50 value of 11 µM its toxicity is