Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

• Vincent Fagan,
• Istvan Toth and
• Pavla Simerska

Beilstein J. Org. Chem. 2014, 10, 1741–1748, doi:10.3762/bjoc.10.181

• , Australia 10.3762/bjoc.10.181 Abstract A novel convergent synthetic strategy for the construction of multicomponent self-adjuvanting lipopeptide vaccines was developed. A tetraalkyne-functionalized glucose derivative and lipidated Fmoc-lysine were prepared by novel efficient and convenient syntheses. The

• [30]. The lipo-amino acids used previously for synthesis of the LCP system [31] were prepared by a multistep synthesis which resulted in a racemic mixture. In the current study, enantiomerically pure lipidated Fmoc-lysine (8) was synthesized and used to prepare the lipidic adjuvanting moiety

• . Treatment of commercially available Fmoc-Lys-OH with lauroyl chloride, in the presence of diisopropylethylamine (DIPEA), gave lipidated Fmoc-lysine (8) in 35% yield after flash chromatography (Scheme 3A). The low yield could be attributed to the formation of a significant amount of a dimeric lysine

Orthogonal dual thiol–chloroacetyl and thiol–ene couplings for the sequential one-pot assembly of heteroglycoclusters

• Michele Fiore,
• Gour Chand Daskhan,
• Baptiste Thomas and
• Olivier Renaudet

Beilstein J. Org. Chem. 2014, 10, 1557–1563, doi:10.3762/bjoc.10.160

• α-D-ManSH 1 and β-D-GlcNAcSH 2 were prepared from the corresponding bromo peracetyl and chloro peracetyl sugars by treatment with potassium thioacetate followed by de-O-acetylation under standard conditions [24]. Cyclopeptide 3 displaying two orthogonal functionalities, i.e., four lysine residues

• functionalized with Alloc groups [27] pointing on the upper face, and two lysine residues protected with chloroacetyl moiety at the lower face has been prepared. To evaluate the importance of the reaction sequences, we first performed the TEC reaction using α-D-ManSH 1. This reaction was carried out in a mixture

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

• were selected as target molecules (Figure 1). In conjugate 2 the carboxylic acid function of the isoglutamine of the MDP is linked to the N-terminal amine of the antigenic peptide. In conjugate 3 the same acid function of the MDP connects to the C-terminal lysine of the antigenic peptide. The 3

• % yield. With MurNAc building block 10 and 16 in hand, the solid-phase peptide synthesis of the MDP-antigen conjugates 2–5 was undertaken (Scheme 2). Commercially available Fmoc protected amino acids equipped with standard acid labile protective groups were used. The side chain of the C-terminal lysine of

• and two equivalents of DIPEA (Scheme 2). Next, the resin was treated with a solution of 3% TFA in DCM to selectively remove the Mtt protective group from the side chain of the C-terminal lysine. The resulting free amine was consecutively elongated with Fmoc-D-isoglutamine, Fmoc-L-alanine and MurNAc 10

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• interaction with the target site. GlycoPEGylation of proteins PEGylation of proteins is usually performed on the ε-amine group of lysine or on the unprotected α-amino of the N-terminal amino acid using N-hydroxysuccinimidyl (NHS) activated PEGs or aldehyde PEGs. This conjugation leads to heterogeneous

• products, depending on the number of lysine residues in the molecule. Random PEGylation may have undesired steric effects, shielding active sites in the protein or disrupting its tertiary structure [24]. PEGylation may be also directed to the side-chain amide nitrogen of Asn. In order to improve the

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• ]. Chemical synthesis of lipidated peptides is mostly performed by SPPS using the Fmoc/t-Bu strategy allowing for selective and efficient modification. Fatty acids can be incorporated into the peptide sequence at the N-terminus [98], at lysine [99] or cysteine side chains [100] and by esterification [101]. A

• detailed overview of chemical approaches to obtain lipidated peptides containing examples for each strategy is given by Zhang et al. [97]. In many cases, the on-resin lipidation is carried out at the lysine side chain [102][103]. Therefore, the peptide backbone can be synthesized by automated SPPS and the

• Nε-group of the lysine that should be modified, is protected specifically by a side-chain protecting group that is orthogonal to the Fmoc group. Acid-labile groups as Mmt [41] and Mtt (4-methyltrityl) [104] (classical cleavage with 1% TFA in DCM (dichloromethane)), base-labile groups as ivDde (1-(4,4

N,N'-(Hexane-1,6-diyl)bis(4-methyl-N-(oxiran-2-ylmethyl)benzenesulfonamide): Synthesis via cyclodextrin mediated N-alkylation in aqueous solution and further Prilezhaev epoxidation

• Julian Fischer,
• Simon Millan and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 2834–2840, doi:10.3762/bjoc.9.318

• adequate phase transfer catalysts and the cyclodextrin–guest complexes were characterized by 1H NMR and 2D NMR ROESY spectroscopy. Finally, the curing properties of the diepoxide with lysine-based α-amino-ε-caprolactam were analyzed by rheological measurements. Keywords: alkylation; cyclodextrins; epoxy

• method to alternative sulfonamide based diepoxides, focusing on one characteristic example. Furthermore, the polymerization of these types of diepoxides was investigated with lysine-based α-amino-ε-caprolactam through rheological measurements. Results and Discussion N,N'-(Hexane-1,6-diyl)bis(4

• was reacted in a ring-opening polymerization with the primary amine α-amino-ε-caprolactam (8). 8 was synthesized by cyclization of lysine (7) (Scheme 2). Hence, an increase of the reactivity of the primary amino group towards the epoxide function compared to the amino groups in native lysine was

Oligomeric epoxide–amine adducts based on 2-amino-N-isopropylacetamide and α-amino-ε-caprolactam: Solubility in presence of cyclodextrin and curing properties

• Julian Fischer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 2803–2811, doi:10.3762/bjoc.9.315

• primary amino function of glycine methyl ester hydrochloride (1) with di-tert-butyl dicarbonate [21], further amidation with isopropylamine (3), and finally deprotection in acidic solution. We also synthesized as a further monomer the lysine based primary amine α-amino-ε-caprolactam (7) through

• oil pump over P4O10. Glycine methyl ester hydrochloride (98%) and L(+)-lysine monohydrochloride (99+%) were purchased from Acros Organics, di-tert-butyl dicarbonate (97+%) and isopropylamine (99+%) were obtained from Alfa Aesar, glycerol diglycidyl ether and deuterium oxide (D2O, 99.9% D) were

• (acetone) m/z: 117.1 [M + H]+. Synthesis of 7 [22]: A mixture of 20 g (109.5 mmol) L-lysine monohydrochloride (6), 4.38 g (109.5 mmol) sodium hydroxide, 60 g (589 mmol) aluminium oxide and 300 mL n-butanol is heated to reflux for 48 h in a reaction vessel equipped with a water trap. Subsequently, the

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• that accounts for both dynamic and static quenching. Free amino acids at high concentrations can also quench fluorophores. To access the propensity for NBDM to be quenched by amino acids, we measured fluorescence in the presence of varying concentrations of alanine, glutamine, lysine, tyrosine

• , methionine and histidine. As expected, the amino acids lacking functionality known to quench fluorophores (alanine, glutamine and lysine) did not quench NBDM at concentrations as high as 50 mM. Interestingly, tyrosine did not quench NBDM fluorescence even at concentrations as high as 2 mM (solubility limit

Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides

• Christian Dollendorf,
• Martin Hetzer and
• Helmut Ritter

Beilstein J. Org. Chem. 2013, 9, 1652–1662, doi:10.3762/bjoc.9.189

• -methacryloylglycylglycine, copolymers of DMAEMA and 1,4-bis(2-thiobenzoylthio)prop-2-yl)benzene, or cross-linked poly(L-lysine) [46][47][48]. In the current work, we describe the synthesis of a novel redox-responsive polycationic hydrogel by cross-linking copolymers of N,N-diethylacrylamide (DEAAm) and DMAEMA with a

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• agar piece was used to inoculate the preculture, 7 mL RapV7 Seed Medium [47] supplemented with 0.16 mL 20% glucose, and cultivated for 48 h at 180 rpm and 28 °C. The main culture in 7 mL MD6 medium [47] (supplemented with 0.35 mL 40% fructose and 0.1 mL L-lysine (140 mg/mL)) was mixed with feeding

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• -acid sequence. We chose cRGD pentapeptide 1b derived from lysine precursor 1a, as cRGD’s intensively studied by the Kessler group [6][7][8][9] are well-established cell-recognition motifs that can trigger integrin-mediated cell adhesion [9]. Because of the high potential to stimulate this, these RGD

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• epigenetic modifications, their biological outcomes, and how their misregulation is involved in diseases such as cancer [1][2]. The dynamic post-translational acetylation/deacetylation of histone proteins is one of the most commonly studied epigenetic events, and occurs at specific lysine residues on the N

• -terminal histone tails, which project out from the nucleosome (the fundamental repeating unit of chromatin). Acetylation/deacetylation of such lysine residues is achieved by the action of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Histone deacetylation by HDACs causes

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• action of antimicrobial peptides, which are generally poorly understood. Several scaffolds, such as linear and cyclic peptides, alkyne-functionalized dendrimers, a branched lysine core, and also a polymaleic polymer, have been exploited as templates for the synthesis of multivalent antimicrobial peptides

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

• times less toxic than when bound to poly-(L)-lysine. This suggests that the release of a toxic phalloidin species inside the cell includes the enzymatic breakdown of the carrier. In agreement with this we found no difference between the L-configurated and the D-configurated carrier when the linker

• derivative (8 residues) are comparable, we argue that arginine residues are more effective in mediating internalization of phalloidin than are lysine residues. For phalloidin bound to methoxy-polyethylene-glycol we found that cytotoxicity strictly depended on the molecular weight of the polymer chain (Figure

• comparable to those of the most toxic phalloidin derivatives, phalloidin oleate (1e) and phalloidin-poly-(L)-lysine (2e). More importantly, rhodaminyl-phalloidin seems not to be cleaved inside the cell and, through its fluorescence, can report on the structure of its target protein, the actin filaments

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

• includes the selective reduction of nitro groups to amines in the presence of ketones (Scheme 11) [50][51], and the oxidation of benzaldehyde to benzoic acid, albeit with incredibly poor conversion [52]. The conversion of L-lysine (32) to L-pipecolinic acid (33, Scheme 12) has also been investigated by

• -functionalised poly-L-lysine with alkyne tethered glycol-dendrons to form cyclobutenes [84]. The reactions were performed on a sub-millimolar scale, but the precise control over reaction conditions with the flow apparatus allowed for high yields of the complex dendronic products. Nettekoven et al. [85] trialled

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• variety of cargo molecules for therapy and diagnosis, as could be successfully shown for, e.g., cytostatics [1], proteins [2], oligonucleotides [3][4] and nanoparticles [5]. A common feature of CPPs is their typically high content in basic arginine and lysine residues, leading to a positive net charge of

• -293 and MCF-7 was observed. The drastically enhanced uptake of the dimer compared to the monomeric peptide is in contrast to previous studies with the TAT peptide, which is similar to sC18 with respect to the number of arginine and lysine residues and the overall charge of the peptide. Dimerization of

• -butyloxycarbonyl (Boc). Indeed, we did not observe concomitant deprotection of lysine side chains, which was favored by the fact that Mtt groups situated at the N-terminus are even more acid-sensitive than Nε-Mtt groups [25]. The structural analysis of the (sC18)2 conjugates by circular dichroism spectroscopy did

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

• H. Bauke Albada,
• Alina-Iulia Chiriac,
• Michaela Wenzel,
• Maya Penkova,
• Julia E. Bandow,
• Hans-Georg Sahl and
• Nils Metzler-Nolte

Beilstein J. Org. Chem. 2012, 8, 1753–1764, doi:10.3762/bjoc.8.200

• from being understood. Importantly, the activity of these peptides was comparable in two different media, namely the bacterial Mueller–Hinton (MH) and in the richer cell culture medium. Interestingly, replacement of the arginine residues with lysine residues resulted in an almost completely inactive

The Amadori rearrangement as glycoconjugation method: Synthesis of non-natural C-glycosyl type glycoconjugates

• Katharina Gallas,
• Gerit Pototschnig,
• Florian Adanitsch,
• Arnold E. Stütz and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2012, 8, 1619–1629, doi:10.3762/bjoc.8.185

• -3-acetamido-D-gluco-heptulose 34 in the pyranoid form and in 50% yield after purification by column chromatography. Methyl 6-aminohexanoate hydrochloride gave the corresponding α-pyranose 35, albeit in only 25% yield. With the α-N-Boc protected L-lysine derivative Boc-L-Lys(Z)-OMe, the Amadori

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• units, each amino acid residue needs to be specifically addressed. Furthermore, all three amino acids should have side chains long enough to avoid steric hindrance between the moieties and the core. Thus, homo-β-lysine was chosen as the underlying amino acid to build up the scaffold allowing side-chain

• functionalization by amide bond formation. To protect the lysine side chain for selective and orthogonal amide-bond formation following the solid-phase peptide synthesis (SPPS), the protection groups fluorenylmethoxycarbonyl (Fmoc) and carbobenzyloxy (Cbz) were applied. Alteration of the amine in the third β

• silver benzoate and water as a nucleophile [19][20][21][22][23] yielding the homo-β-lysine derivatives 1 and 2 alongside the azide β-amino acid 3 (Figure 2). In previous studies, synthesis of the cyclic β-tripeptide scaffold was provided by cyclization of the linear β-tripeptide obtained by solution

Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations

• John B. Bremner,
• Paul A. Keller,
• Stephen G. Pyne,
• Mark J. Robertson,
• K. Sakthivel,
• Kittiya Somphol,
• Dean Baylis,
• Jonathan A. Coates,
• John Deadman,
• Dharshini Jeevarajah and
• David I. Rhodes

Beilstein J. Org. Chem. 2012, 8, 1265–1270, doi:10.3762/bjoc.8.142

• , then provided access to the key intermediate amines 6a–g (Scheme 1). Diimide-mediated coupling of the previously reported lysine containing (S)-binaphthyl acid derivative 7 [8] then afforded the protected tripeptides 8a–g. Removal of the Pmc (or Pbf) and Boc protecting groups in one pot was then

Multistep organic synthesis of modular photosystems

• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2012, 8, 897–904, doi:10.3762/bjoc.8.102

• NDI 18 of initiator 2, designed to initiate and template for SOSIP, was accessible from NDA 13 as well. The synthesis of NDI 19 by microwave-assisted imidation with Boc-protected lysine 20 has been reported before in the literature [15]. Reaction with Cbz-hydrazine gave the Cbz-protected NDI hydrazide

• diphosphonates in NDI 24 gave 18, which was reacted in situ with NDI 12 to yield initiator 2. Synthesis of propagators The synthesis of propagator 3 starts with NDA 13 as well (Scheme 2). Diimidation with Cbz-protected lysine 25 gave the diacid 26. Activation with EDC, HOBt and TEA was followed by the reaction

• naphthalenetetraesters (cNTEs). Nucleophilic core-substitution with ethanolate gave cNTE 34 as described in the literature [16]. NTE 34 was subjected to basic ester hydrolysis followed by diimidation with lysine 25. From this point, the synthesis of cNDI propagator 4 was analogous to the synthesis of NDI propagator 3

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• microbe and lectin binding studies, glycopeptide based glycoclusters/dendrimers were applied, employing linear peptide backbones, cyclic peptide scaffolds or multi-lysine scaffolds [106][107][108][109][110][111][112][113][114][115][116][117][118]. The pentavalent cholera toxin protein secreted by Vibrio

• further increased [137][138][139]. In one study, the FimH inhibition of mannosylated di- and tetravalent lysine core dendrimers resulted in 455- and 2000-fold increases relative to a monovalent mannose residue [114]. The observed multivalency effects are not fully understood. In a recent study, mannose di

Investigation of the network of preferred interactions in an artificial coiled-coil association using the peptide array technique

• Raheleh Rezaei Araghi,
• Carsten C. Mahrenholz,
• Rudolf Volkmer and
• Beate Koksch

Beilstein J. Org. Chem. 2012, 8, 640–649, doi:10.3762/bjoc.8.71

• peptide (Acid-pp) and a lysine-rich chimeric B3β2γ sequence. These systems have a high propensity for heterooligomerization (Figure 1). In B3β2γ, the two central turns of the α-helix are substituted by a pentad of alternating β- and γ-amino acids. Our previous study revealed the heteromeric assembly of

Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations

• Baptiste Thomas,
• Michele Fiore,
• Isabelle Bossu,
• Pascal Dumy and
• Olivier Renaudet

Beilstein J. Org. Chem. 2012, 8, 421–427, doi:10.3762/bjoc.8.47

• ., (CH2)4) of the lysine (Lys) and the norleucine (Nle) side chain. Synthesis of heteroglycoclusters of the 3:1 series. Reagents and conditions: (i) 1a, 2a or 3a, 0.1% TFA in H2O; (ii) 1b, 2b or 3b, Cu micropowder, t-BuOH, AcONH4 100 mM pH 7.4 (1:1, v/v). Outcome of the orthogonal ligation procedure

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• inhibit proteases. A signature of the group is the conserved ureido linkage connecting the side-chain amino acid to D-lysine. The corresponding NRPS gene cluster was first analyzed in the strain Anabaena sp. 90 and revealed a new mechanism underlying production of diverse variants by the same strain: Two

• /MvdD) and one ω-amide linkage between lysine and aspartate (MdnB/MvdC) (Figure 10) [64][65]. Microviridins can be heterologously produced in E. coli [65]. Cyclizations occur in a strictly defined order. Ring size and composition of the microviridin core peptide is invariant [66], whereas N-terminal and