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

• ) and human colon cancer cells (HT-29), is GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] (K2). Recent studies demonstrated that the butyrilation of the lysine in position 4 not only leads to an increased in vitro but also to an enhanced in vivo antitumor activity [29][30]. In order to achieve a better

• homogenate. Results and Discussion Synthesis of oxime bond-linked GnRH-III–[4Ser/Lys(Bu), 6Aaa, 8Lys(Dau=Aoa)] bioconjugates The GnRH-III bioconjugates were prepared as shown in Scheme 1. All peptides were synthesized by standard Fmoc-SPPS using orthogonal lysine protecting groups. Fmoc-Lys(Dde)-OH was

• . Furthermore, the incorporation of an acetylated lysine instead of the native serine in position 4 decelerated the degradation by α-chymotrypsin which catalyzed the hydrolysis of the peptide bond exclusively between 3Trp and 4Aaa. A similar effect was observed for GnRH-III conjugates in which the ε-amino group

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• such intermediates. By selecting the appropriate reaction conditions (various pH and temperatures), they were able to alkylate free amino acids, e.g., glycine (Gly), L-serine (Ser), L-cysteine (Cys), L-lysine (Lys), L-tyrosine (Tyr) and glutathione (Glu) in aqueous solution to isolate 55 (Scheme 8

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

• further developments as ON prodrugs. Similarly, Damha reported on the synthesis of ONs containing amino acid-acetal esters at the 2’-OH, particularly with lysine for its positive charge (Figure 3B) [55]. Unfortunately, 2’-O-acetal ester ONs with lysine, alanine and phenylalanine could not be isolated with

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• (Figure 6) [40]. To ensure a close contact between the two labels, amino acids with opposite charges (typically glutamic acid and lysine) are usually placed in the vicinity of the labels. This was the practice originally used by the Boston Probe design and has been followed since by many others [40]. In

• ]. On the other hand, a polycationic comb-type dextran-poly(lysine) copolymer was shown to strongly promote the strand exchange of PNA–DNA duplexes by another DNA strand [110]. The equilibrium of the strand displacement reaction lies on the side of the more stable duplex, and so the original strand

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• P1 position is occupied by a phenylalanine residue. Lysine residues were introduced at both ends of the peptide sequence to enhance solubility, and o-aminobenzoic acid (Abz) at the N-terminus serves as a fluorescence label. Alanine residues in positions P3, P3’, and P4’ act as spacers as the peptide

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• hydrolysis acceleration from the proximal lysine charge (9b, 10b vs 8b, factor ≈ 30) is lower than the α-NH2/NH3+ hydrolysis acceleration in the classical studies of α-amino acid esters (factor ≈ 100–150) [58]. The hydrolysis rate can thus be further tuned by changing the proximity of the positive charge to

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• propargylamine 7p is not stable under the conditions, which are necessary to cleave the thioether [100][101]. Synthesis of propargylamines with basic functional groups in the side chain Very often, basic amino acids, like lysine or arginine are found in the catalytic center of enzymes. Therefore, propargylamines

• 14w have been successfully applied as inhibitors of β-glucosidases [107] and hexosamidases [108], this intramolecular Huisgen reaction could be exploited to develop novel enzyme inhibitors. In order to get access to propargylamines with the side chains of lysine, ornithine and arginine, azide 7wx

• -induced TMS cleavage could also be successfully applied in the synthesis of the lysine analogous propargylamine 7vy from 5v but could never be reproduced in the formation of other propargylamines, like the tert-butyl-substituted compound 7e, under identical reaction conditions. The amine groups of 7wy and

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• procedure was applied to prepare a molecular receptor of lysine residue [171]. Following this procedure, the monodealkylation can be explained by the formation of a sodium salt that due to electronic factors prevent the second dealkylation. However, the protonation of this anionic compound 46 by ion

Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

• Shital Kumar Chattopadhyay,
• Suman Sil and
• Jyoti Prasad Mukherjee

Beilstein J. Org. Chem. 2017, 13, 2153–2156, doi:10.3762/bjoc.13.214

• antimalarial and histone deacetylase inhibitory (HDACi) properties [1][2]. It has been suggested [3] that the terminal carbonyl group in members of this family (e.g., in 2) functionally mimics the C-8 keto group of the acetylated lysine residue (3) of histones as a part of their biological activity and

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• output, creating a binary signal. Finally, we used oppositely charged polyelectrolytes to form complex coacervates in Figure 6c. Coacervates are formed in the second CSTR only in the absence of Tr, as Tr catalyzes the lysine-functionalized polycation. This demonstrates that the relatively long

Investigation of the action of poly(ADP-ribose)-synthesising enzymes on NAD⁺ analogues

• Sarah Wallrodt,
• Edward L. Simpson and
• Andreas Marx

Beilstein J. Org. Chem. 2017, 13, 495–501, doi:10.3762/bjoc.13.49

• experiments is summarised in Table 1. For illustration, Figure 3 shows the processing of derivative 1 by all the four ARTDs tested. Of note, it was previously reported [21] that the incubation of proteins with NAD+ analogues may result in non-enzymatic Schiff base formation of ADP-riboses with lysine residues

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

• Bemba Sidi Mohamed,
• Christian Périgaud and
• Christophe Mathé

Beilstein J. Org. Chem. 2017, 13, 251–256, doi:10.3762/bjoc.13.28

• organic chemicals synthesis, furfuryl alcohol is a raw material for the production of tetrahydrofurfuryl alcohol, which is an intermediate for the synthesis of 1,2- and 2,5-pentanediols and their derivatives and an agent for the manufacture of fragrance, vitamin C and lysine [1][2]. Furfuryl alcohol is

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• support its occupancy by a remarkably conserved lysine residue (K517 in PheA) [19], whose side chain counters the negative charge of the substrate’s carboxy group [14][20]. Also, the relationship between the expected substrate and the nonribosomal code of AulA-A2 posed itself as a conundrum. The first

Inhibition of peptide aggregation by means of enzymatic phosphorylation

• Kristin Folmert,
• Malgorzata Broncel,
• Hans v. Berlepsch,
• Christopher H. Ullrich,
• Mary-Ann Siegert and
• Beate Koksch

Beilstein J. Org. Chem. 2016, 12, 2462–2470, doi:10.3762/bjoc.12.240

• intramolecular Coulombic repulsions between negatively charged glutamate residues and the phosphate, or in electrostatic pairing with positively charged lysine or arginine residues, resulting in the perturbation of higher ordered secondary structures [53]. The impact of electrostatics on peptide and protein

From supramolecular chemistry to the nucleosome: studies in biomolecular recognition

• Marcey L. Waters

Beilstein J. Org. Chem. 2016, 12, 1863–1869, doi:10.3762/bjoc.12.175

• thus studied the influence of lysine methylation and the significance of the positive charge in our β-hairpin model systems [23][24], and then moved into studying the actual protein–peptide interaction as well, providing the first definitive evidence that cation–π interactions provided the dominant

• sequence. This turned out to be an ideal problem to address using DCC, and we have now developed a number of synthetic receptors for methylated lysine and arginine that have applications as sensors for these modifications (Figure 6). Lessons learned As a child, my parents said that I “marched to my own

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• addition, our binding predictions for compounds 1n and 1q indicated that the ribose moiety is linked to Lys215 by hydrogen bonding between the hydroxy groups and the lysine terminal nitrogen. As the ribose is being stabilized, the triazole ring is correctly positioned between the surrounding hydrophobic

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• number of cyanobacteria [99][100][101][102][103]. Members of this family can feature both macrolactams and macrolactones, and both of these are introduced by ATP-grasp ligases [88]. These macrolactams are formed by the condensation between the side chains of lysine and glutamate residues, whereas the

• streptococcal RiPP that is involved in bacterial communication [127]. Here, StrB catalyses the formation of a carbon–carbon bond between lysine and tryptophan side chains [25]. This is proposed to be mechanistically similar to thioether bond formation, although the role of the second [4Fe–4S] cluster is likely

• to differ slightly as it is unlikely that either carbon initially bonds to this cluster (Figure 10B). Instead, a radical on the lysine β-carbon (generated by 5’-dA• hydrogen abstraction) attacks C-7 on the tryptophan ring. This generates an indolyl radical that can lose an electron to the second [4Fe

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• context, the modification of natural peptides and proteins is highly attractive, and it has been the target of intensive research in the last decades (Figure 1) [6][7][8][9][10][11]. The functionalization of highly reactive cysteine, lysine and the N-terminus has been particularly successful [12][13][14

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• tweezers 19 and 20 are water-soluble but tend not to self-associate [33]. This has allowed their use in a range of biomolecular recognition applications, which appear quite promising. For example, tweezer 20, also called CLR01, has been found to bind the accessible lysine and arginine groups of proteins

• , materials and medicine.” Some of the examples presented herein illustrate the potential of the supramolecular approach to lead to advanced therapeutic agents. In particular the Klärner molecular tweezers that complex lysine-containing peptides may lead to agents that dissolve Alzheimers plaques or inhibit

Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

• Ahmed Mahal,
• Stefano D’Errico,
• Nicola Borbone,
• Brunella Pinto,
• Agnese Secondo,
• Valeria Costantino,
• Valentina Tedeschi,
• Giorgia Oliviero,
• Vincenzo Piccialli and
• Gennaro Piccialli

Beilstein J. Org. Chem. 2015, 11, 2689–2695, doi:10.3762/bjoc.11.289

• ; 7 days). Cells were cultured in an atmosphere of 5% CO2. The culture medium was changed every 2 days. For microfluorimetric studies with Fura 2-AM, cells were seeded on glass coverslips (Fisher, Springfield, NJ, USA) coated with poly-L-lysine (5 μg/mL) (Sigma, St. Louis, Missouri, USA) and used at

• least 12 h after seeding. Intracellular Ca2+ concentration ([Ca2+]i) was measured by single cell computer-assisted video QImaging [43]. Briefly, differentiated PC12 cells cultured on poly-L-lysine-coated glass coverslips were loaded with 10 µM Fura-2AM for 1 h at 22 °C in Krebs–Ringer saline solution

Assembly of synthetic Aβ miniamyloids on polyol templates

• Sebastian Nils Fischer and
• Armin Geyer

Beilstein J. Org. Chem. 2015, 11, 2646–2653, doi:10.3762/bjoc.11.284

• to the two amine groups of a lysine. Only covalently linked dimeric peptides with parallel peptide strands showed a cooperative folding behavior. The correct relative orientation of the individual peptide strands proved to be crucial for their cooperative and reversible un/folding behavior to mimic

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• for lysine in these positions, while WW2 more strictly requires the arginine. Possibly, the hybrid resonance of the guanidinium group in the arginine is more important in the case of WW2 compared to WW1. The peptide WPPPPRVPR was further on taken as a basis for exploring the effect of multivalent

Sequence-specific RNA cleavage by PNA conjugates of the metal-free artificial ribonuclease tris(2-aminobenzimidazole)

• Friederike Danneberg,
• Alice Ghidini,
• Plamena Dogandzhiyski,
• Elisabeth Kalden,
• Roger Strömberg and
• Michael W. Göbel

Beilstein J. Org. Chem. 2015, 11, 493–498, doi:10.3762/bjoc.11.55

• were attached to one, 15mers to two lysine units placed at the C-terminus. For conjugation, the Fmoc-protected 6-aminohexanoic acid 9 was bound to the PNA at the terminal amino group as a linker. After deprotection of the linker’s amino function, tris(2-aminobenzimidazole) was attached. In both steps

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• that amino acid chemistry has fostered the development of a number of specialized methodologies to handle the manifold functional groups present in the most common amino acids. A salient example is the copper chelation chemistry originally introduced by Kurtz in 1941 to isolate lysine from protein

• hydrolysates [5]. Conversion of amino acids to their copper salts elegantly masks both amino acid functionalities, thus protecting them during a subsequent alkaline acylation reaction that targets the side-chain functionality selectively. The side-chain-acylated lysine can then be liberated by decomposition of

• the copper salt with hydrogen sulfide. This methodology has subsequently been employed in a more generic sense as a preparative method for synthesis of acrylic side-chain derivatives of amino acids such as lysine, ornithine, tyrosine and serine [6][7][8], having modified the original technique by

Versatile synthesis of amino acid functionalized nucleosides via a domino carboxamidation reaction

• Vicky Gheerardijn,
• Jos Van den Begin and
• Annemieke Madder

Beilstein J. Org. Chem. 2014, 10, 2566–2572, doi:10.3762/bjoc.10.268

• lysine derivatives onto nucleosides via a straightforward and easy domino carboxamidation reaction. Previously the groups of Gait and Eaton [41][42][43] have used this reaction to couple histamine or simple amine derivatives to both 5-iodo-2’-deoxyuridine and purine nucleosides. Although a large number

• of histidine (imidazole) and lysine (cationic amine) are known to be present in numerous enzyme active sites and capable of general acid–general base catalysis, we have finally chosen to modify a nucleoside with a lysine amino acid derivative as a third example of our current strategy, as shown in

• Scheme 3. Protected lysine 10 is commercially available and was coupled with the TBDMS-protected nucleoside 1 to afford product 11 in high yield. After deprotection of the tert-butyldimethylsilyl protecting groups using the above described protocol, modified nucleoside 12 could be selectively protected