Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

Synthesis and bioactivity of pyrrole-conjugated phosphopeptides

• Qiuxin Zhang,
• Weiyi Tan and
• Bing Xu

Beilstein J. Org. Chem. 2022, 18, 159–166, doi:10.3762/bjoc.18.17

• from 1, suggest that the morphological transition of the peptide assemblies resulted from enzymatic reaction likely is responsible for disrupting cellular processes to inhibit cells. Other factors, such as endocytosis of the phosphopeptides [74] and the cellular localization of the peptide assemblies

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• , ASOs carrying the novel guanidinium modification were mainly localized in the cytoplasm, indicating that the ASOs are taken up by endocytosis but are retained in part in the endocytic vesicles [112]. Utilizing the phosphorus atom as an attachment point for cationic aminoalkyl groups has been employed

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• ][159][160]. Looking forward, conjugation of PNA with various delivery enhancing compounds, most notably cell-penetrating peptides (CPP) that deliver the conjugates mainly through endocytosis (Figure 11) has become one of the most promising approaches to improving cellular uptake of PNA [161][162

• covalent conjugation of PNA to delivery enhancing compounds. Cell-penetrating peptides derived from natural proteins: The initial success of PNA delivery involved PNA conjugates taken up by receptor-mediated endocytosis. Pardridge and co-workers successfully demonstrated in vivo delivery and blood-brain

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• has been shown to be specific for, and internalized by the CCR5 receptor [34]. Similarly, it has been found that the A-1 aptamer specifically recognizes gp160 and that it may be internalized through receptor-mediated endocytosis [35]. Both the G-3 and A-1 aptamers have been conjugated to small

• complexation with cluster of differentiation 4 (CD4) and CCR5 or C-X-C motif chemokine receptor 4 (CXCR4) host cell surface receptors [35]. As such, gp160 expression on the host cell surface receptor may not be as adept at facilitating cell entry via receptor-mediated endocytosis. Although in 2009, Zhou et al

• . observed by confocal microscopy that the A-1 aptamer entered gp160-positive cells and suggested that receptor-mediated endocytosis could be the mechanism of entry, such a notion was not definitively demonstrated as the mechanism of uptake [35]. In addition, observed differences between these aptamers could

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• for the thiol-mediated uptake, beginning with a dynamic covalent disulfide exchange with exofacial thiols, followed by either endocytosis or the direct crossing of membranes into cytosols through successive thiolate–disulfide exchange reactions or micellar pores (Figure 5b) [61]. Anionic glutamate was

Plasma membrane imaging with a fluorescent benzothiadiazole derivative

• Pedro H. P. R. Carvalho,
• Jose R. Correa,
• Karen L. R. Paiva,
• Daniel F. S. Machado,
• Jackson D. Scholten and
• Brenno A. D. Neto

Beilstein J. Org. Chem. 2019, 15, 2644–2654, doi:10.3762/bjoc.15.257

• transduction, apoptosis and even necrosis [8][9][10]. The monitoring of plasma membranes, their biophysical properties, endocytosis/exocytosis of several types of molecules, as well as their dynamic changes, may be performed by using fluorogenic organic dyes or derivatives thereof [11][12][13][14][15]. The

• previously stained with the fluorescent compound. There is no way to eliminate this fluorescent signal because of the constitutive presence of endosomes in mammalian cells. Cancer cells have, in addition, an accelerated metabolism and high endocytosis index [63]. Endocytosis is known to be the cellular event

Targeted photoswitchable imaging of intracellular glutathione by a photochromic glycosheet sensor

• Xianzhi Chai,
• Hai-Hao Han,
• Yi Zang,
• Jia Li,
• Xiao-Peng He,
• Junji Zhang and
• He Tian

Beilstein J. Org. Chem. 2019, 15, 2380–2389, doi:10.3762/bjoc.15.230

• endocytosis and significantly lower the background signal for intracellular fluorescence imaging [25][26]. Upon the incubation of the dithienylethene fluorescence reporter Glyco-DTE with 2D MnO2 nanosheets, the reporter was adsorbed on the surface of the nanosheets, forming the Glyco-DTE@MnO2 photochromic

Fluorescent phosphorus dendrimers excited by two photons: synthesis, two-photon absorption properties and biological uses

• Anne-Marie Caminade,
• Artem Zibarov,
• Eduardo Cueto Diaz,
• Aurélien Hameau,
• Maxime Klausen,
• Kathleen Moineau-Chane Ching,
• Jean-Pierre Majoral,
• Jean-Baptiste Verlhac,
• Olivier Mongin and
• Mireille Blanchard-Desce

Beilstein J. Org. Chem. 2019, 15, 2287–2303, doi:10.3762/bjoc.15.221

• deciphering the mechanism of action of these dendrimers, in particular for monitoring the intracellular penetration. This fluorescent dendrimer avidly binds to the cell membrane during the first 10 min of exposure and after 24 h, it has penetrated the cell, probably by endocytosis, and went in the

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

• endo-lysosomal compartments after NPY Y1 receptor-mediated internalization of the peptide–toxin conjugate into the target cells via clathrin-dependent endocytosis. In the following, in vitro studies were conducted to verify if this expectation is met, and to study the biological consequences thereof

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

• − 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

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• then migrates either via a classical endocytosis pathway, or via retrograde transport through the secretory pathway into the cytosol, where the A domain can exert its toxic property. AB5 toxins are abundant in many pathogens and the B domain is a carbohydrate-binding domain for cell-surface binding

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

• receptor-mediated endocytosis of the receptor–conjugate complex and (iv) the desensitization of GnRH-R [4][18]. The 3Trp-4Ser bond is a most susceptible site to be cleaved by proteolytic enzymes (e.g., chymotrypsin, angiotensin-converting enzyme). The substitution of Ser4 by its N-methyl analog (N-Me-Ser

• (Ac)]-GnRH-III(Dau=Aoa). Dau served as a positive control in this experiment and showed a high level of intracellular fluorescence. Considering that Dau is a small molecule and can diffuse through the plasma membrane while the conjugates can enter the cells by receptor-mediated endocytosis with low

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

• cargo and CPP or by forming non-covalent complexes. Notably, the mechanism of cell entry is still not fully understood, and can only hardly, if in any case, be predicted [9]. In fact, whereas one of the main mechanisms is endocytosis, there exist also CPPs that translocate through cellular membranes by

• chimeric peptides enter the cells concentration-dependent by direct penetration or by endocytosis, followed by an endosomal release, which could already be shown for other sC18 derived CPP variants [20]. To get an idea about the involvement of endocytotic processes during peptide internalization, uptake

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

• usually inserted into the cell via endocytosis and then they are transported to intracellular compartments with higher concentration of enzymes and lower values of pH, where they disassociate from the receptor and afterward from the anticancer agent. The most representative examples of peptides utilized

• which may cyclize through the formation of intramolecular disulfide bonds [39]. The most commonly used linear peptides and cyclic peptides that can be delivered inside cancer cells via endocytosis and one that smuggles into glioma tissues via transcytosis (angiopep-2) are presented below: Arginine

• ), HER3 (ErbB-3) and HER4 (ErbB-4). Cohen and Rita Levi-Montalcini shared the Nobel Prize in Medicine in 1986 for discovering growth factors. EGFR is upregulated in a wide pool of cancer tissues and is able to enter cells usually via clathrin-mediated endocytosis [72]. Many peptides have been discovered

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

• positive [17]. The effect of the new drug conjugates was compared with the toxicity of free Dau and our lead compound Dau=Aoa-GFLGK(c[KNGRE]-GG)-NH2 (K). The bioconjugates enter cancer cells most likely by receptor-mediated endocytosis (at least at lower micromolar concentration) followed by the release of

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

• efficiency of the DDS. Next to these findings, we could systematically specify the receptor-mediated endocytosis pathway for GnRH-III-[4Lys(Bu), 8Lys(Dau=Aoa)] which is also representative for other Dau–GnRH-III bioconjugates. Based on our results, we can assume that the GnRH-III bioconjugates specifically

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

• hepatocytes, where the transporting protein OATP1B3 internalizes amatoxins resulting in high liver toxicity [2][3]. This strong toxicity in the presence of endocytosis mediators allowing cell permeation, aroused interest towards the use of α-amanitin as a payload for targeted cancer therapy. In 1981, Davis

• , unfavorable pharmacokinetics (low tissue diffusion and low accumulation rate) and possible elicitation of immune response [6]. By conjugation to a specific cell-membrane-receptor ligand, the toxin can be delivered at the tumor site and internalized through receptor-mediated endocytosis. In 2013, Reshetnyak

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• ., phosphate groups) in the molecule [65][66][67]. It has been just recently shown that TLR4 is not a sole receptor protein accountable for cellular responses induced by LPS. A number of pro-inflammatory effects such as autophagy, endocytosis and oxidative burst are induced by the LPS-mediated activation of an

Fluorescent carbon dots from mono- and polysaccharides: synthesis, properties and applications

• Stephen Hill and
• M. Carmen Galan

Beilstein J. Org. Chem. 2017, 13, 675–693, doi:10.3762/bjoc.13.67

• where found to localise in the cytoplasm and particularly around the nucleus. Due to the large amounts of internalisation a receptor-mediated endocytosis was proposed. The particles were used as fluorescent probes to target CD44 high expression in tumour cells, opening the door for these types of

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

• NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis. Keywords: asialoglycoprotein receptor; cholesterol; cyclodextrin; lactose; Niemann–Pick type C disease; Introduction The Niemann–Pick type C (NPC) disease is a lipid storage disorder with the accumulation of membrane

• clearance of glycoproteins containing terminal galactose or GlcNAc residues from the circulation [12]. Hence, galactosylated nanocarriers have been utilized for the selective delivery of drugs to the liver via ASGPR-mediated endocytosis [13]. In fact, ASGPR-mediated endocytosis is one of the promising

• , but also cholesterol trafficking are necessary. Conclusion In this study, we developed multi-Lac-β-CD (DSL5.6) to reduce cholesterol levels in NPC-like HepG2 cells. The multi-Lac-β-CD (DSL5.6) was internalized in NPC-like HepG2 cells via ASGPR-mediated endocytosis and was found to diminish the

Versatile synthesis of end-reactive polyrotaxanes applicable to fabrication of supramolecular biomaterials

• Atsushi Tamura,
• Asato Tonegawa,
• Yoshinori Arisaka and
• Nobuhiko Yui

Beilstein J. Org. Chem. 2016, 12, 2883–2892, doi:10.3762/bjoc.12.287

• region of the HeLa cells. The 7 puncta is highly co-localized with the LysoTracker Red, indicating that 7 was internalized into the cells via endocytosis and localized in acidic endosomes and lysosomes. This intracellular uptake pathway and localization of 7 is consistent with our previous reports [14

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

• with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and decreased the accumulation of intracellular

• 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

• ]. Actually, the galactosylation of polymers or lipids has been utilized to develop drug carriers with hepatocyte specificity through ASGPR [11]. Therefore, ASGPR-mediated endocytosis seems to be a promising approach to deliver CyDs to hepatocytes for the treatment of hepatosplenomegaly in NPC disease

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• internalization and processing, before reaching the receptor in the cytosol are not yet fully understood [46]. There are indications that PG fragments are internalized via endocytosis and subsequently processed and transported to the cytosol. Because the antigen presentation assay indicates that the NOD2 modified

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117