Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide. Keywords: antibiotic; argyrin

• ; mutasynthesis; NRPS; peptide synthesis; Introduction Resistance to antibiotics is currently a major threat to public health. Especially Gram-negative bacterial pathogens are of concern, due to their widespread development of resistance mechanisms. To address this general antimicrobial resistance problem, new

• Helmholtz Association (HGF, grant no. VH-NG-934), the European Research Council (ERC StG, grant no SWEETBULLETS) and the German Centre for Infection Research (DZIF) is acknowledged. Author Contributions Statement D.C.B.S. and R.S. designed and performed peptide synthesis. D.P. and S.C.W. designed and

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• have been synthesized via solid-phase peptide synthesis and SN2’ reaction on a Morita–Baylis–Hillman (MBH) residue introduced at the N-terminal of a tetrapeptide. This last step takes advantage of the electrophilic feature of the MBH residue and represents a new cyclization strategy occurring. The

Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP)

• Małgorzata Urbańczyk,
• Michał Jewgiński,
• Joanna Krzciuk-Gula,
• Jerzy Góra,
• Rafał Latajka and
• Norbert Sewald

Beilstein J. Org. Chem. 2019, 15, 1581–1591, doi:10.3762/bjoc.15.162

• , agriculture, biomedical cryopreservation [22][23][24]. Results and Discussion Peptide synthesis Starting from ᴅ-(+)-galactose, we obtained the 3,4,6-tri-O-acetyl-ᴅ-galactal in an excellent yield and transformed it into 3,4,6-tri-O-acetyl-2-azido-2-desoxy-α-ᴅ-galactopyranosyl chloride by one pot

• (O)Ac N-terminal), 170.0 (C(O) Gal), 172.2 (C(O) Ala4), 172.7 (C(O) Ala5), 172.8 (C(O) Ala1), 173.2 (C(O) Ala2). Glycosylated building blocks prepared for solid phase peptide synthesis (SPPS). Model AFGP analogues. Conformational preferences of investigated glycopeptides. Conformational preferences

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

• three cell lines was determined as proof for targeted delivery. Results and Discussion Synthesis of tubugi-1 building blocks We established the Ugi reaction as a powerful tool for peptide synthesis and ligation, including the first syntheses of tubulysine derivatives by us and later also others [44][53

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

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• tag; Fmoc-Lys-(Tfa)-OH; prostate cancer and ovarian cancer; solid-phase peptide synthesis; Introduction The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]. The

• ligand for biomarkers, a fluorescent tag and a chelating moiety for tethering cargo in a continuous process using solid-phase peptide synthesis is poorly developed. Traditional solid-phase peptide synthesis methods for preparation of bioconstructs employ orthogonally protected functional moieties present

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

• peptide synthesis (SPPS) using Fmoc/t-Bu strategy with the orthogonal protecting scheme as described before [17][19] and presented in detail in Supporting Information File 1. In all cases, a Mtt (methyltrityl) protecting group was applied to block the side chain of Lys in position 8. For the development

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• bioactivities and/or functions, which has been one of the central topics in the field of chemical biology [16][17][18][19][20][21][22][23][24][25][26]. Since peptide synthesis and oligonucleotide synthesis require different chemistries, such conjugations are typically carried out in the latter stages of the

• supported reactants would be unique alternatives that allow the use of unactivated amino acids or nucleosides. In peptide synthesis, activation of the N-terminus is rather rare, except for some recent encouraging examples [62][63][64][65][66][67][68]; however, this is not the case for oligonucleotide

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• ), homophenylalanine (hPhe), or Tyr; Figure 3). The CSP1 analogs were constructed using standard solid-phase peptide synthesis (SPPS) protocols (see Materials and Methods for SPPS procedures), followed by purification to homogeneity by semipreparative RP-HPLC (see the Supporting Information File 1 for full

• obtained on an Agilent Technologies 6230 TOF LC/MS spectrometer. The samples were sprayed with a capillary voltage of 3500 V and the electrospray ionization (ESI) source parameters were as follows: gas temperature of 325 °C at a drying gas flow rate of 3 L/min at a pressure of 25 psi. Peptide synthesis

• . All the CSP1 analogs were synthesized on a 4-benzyloxybenzyl alcohol (Wang) resin (0.65 mmol/g) pre-loaded with Fmoc-L-Lys(Boc). With the exception of the phenylglycine and norvaline derivatives, the CSP1 analogs were synthesized using standard Fmoc-based solid-phase peptide synthesis (SPPS

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• eventual clinical development, as it displayed reduced hemolytic activity than Dec-NH2 and exhibited selective killing of cancer cells. The ACPs described here represent excellent scaffolds for the generation of potent, non-toxic, and selective anticancer agents. Experimental Peptide synthesis

• , purification and analysis Peptides were synthesized by solid-phase peptide synthesis on Rink Amide resin, with a substitution degree of 0.52 mmol g−1 on a 0.1 mmol scale, using the Fmoc strategy on a peptide synthesizer (PS3 – Protein Technologies) as described by Torres et al. [9][10]. Dry-protected peptidyl

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

• here are shown in Figure 1 and Figure 2. The GnRH derivatives were prepared by solid phase peptide synthesis (SPPS) according to Fmoc/t-Bu strategy (Supporting Information File 1). Three drug molecules, doxorubicin (Dox), daunorubicin (Dau) and methotrexate (Mtx), were employed in the preparation of

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

• initial study for the delivery of the anticancer drug doxorubicin. Results and Discussion Peptide synthesis and analysis of the secondary structure We chose two different nuclear-targeting sequences, on the one hand the N50 peptide, which was derived from the NF-κB/p50 subunit. N50 binds the adaptor

• sequences, as well as sC18* alone. All peptides were readily synthesized via Fmoc/t-Bu solid-phase peptide synthesis, purified, and analyzed by LC–MS methods as previously described [19][20]. Moreover, 5(6)-carboxyfluorescein (CF)-labeled versions were generated (Table 1). As shown in Table 1 and Figures S1

• ), Oxyma, N,N’-diisopropylcarbodiimide (DIC), doxorubicin (DOX) and 5(6)-carboxyfluorescein (CF) were derived from Fluka (Taufkirchen, Germany), Merck (Darmstadt, Germany), Sarstedt (Nümbrecht, Germany), Sigma-Aldrich (Taufkirchen, Germany) and VWR (Darmstadt, Germany). Peptide synthesis All peptides were

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• peptide synthesis using the monomeric 3'-amino-nucleosyl amino acids (S)-56 and (R)-56, respectively, as building blocks. The synthesis of thymidinyl amino acids 56 was again started from a corresponding 5'-aldehyde 57 using Wittig–Horner olefination and catalytic asymmetric hydrogenation as key steps

• accessible by means of chemical synthesis, which is either based on the application of H-phosphonate (for i) or phosphoramidite-based (for iv) DNA synthesis, or on a massively modified version of DNA synthesis (for ii and iii), or on solid phase-supported peptide synthesis (for iv). Studies on the properties

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• ) reagent FPID and (4-MeOC6H4)3P was successfully applied to solid-phase peptide synthesis and cyclic peptide synthesis. Four peptides with biological activities were synthesized through SPPS and the bioactive cyclic heptapeptide pseudostellarin D was obtained via solution-phase peptide synthesis. It is

• worth noting that FPID can be readily regenerated after the peptide coupling reaction. Keywords: cyclic peptide; FPID; hypervalent iodine(III) reagent; recyclable; solid-phase peptide synthesis (SPPS); Introduction The amide bond is one of the most fundamental functional groups in organic chemistry

• reagents, it is still far from ideal because large amounts of chemical wastes are produced during the amide bond formation reaction using these reagents and the coupling reagents cannot be regenerated [10]. Thus, methods for the peptide synthesis which are efficient and atom-economic are still needed

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

• free N-terminus of the peptide during solid phase peptide synthesis. Though, the conjugation site should be carefully selected, since perturbations induced in the peptide structural microenvironment may result in the abolishment of its binding affinity/selectivity to the targeted receptor. The linker

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

• analytical grade or highest available purity. Synthesis of oxime bond-linked GnRH-III–[4Ser/4Lys(Bu), 6Aaa, 8Lys(Dau=Aoa)] bioconjugates The Dau–GnRH-III derivatives were synthesized by solid phase peptide synthesis according to Fmoc/t-Bu chemistry on a Rink-Amide MBHA resin (0.73 mmol/g coupling capacity

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• acids alone. Further, the rate of formation of peptido RNA depends on the structure of the amino acid, and, to a lesser degree, on that of the ribonucleotide [66], so that a very primitive, not yet encoded form of RNA-induced peptide synthesis can occur under conditions that support the formation and

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• tolerant of other functional groups in the oligosaccharide, for example sialic acids [44] and phosphates [45][46] are completely unaffected; the former is perhaps rather surprising since DMC was first developed as a carboxylic acid activating agent for peptide synthesis by Ishikawa [47]! One caveat to the

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

• available purity and used as such. A detailed synthetic strategy for Fmoc-TfIle-OH is described in literature [44]. For the synthesis of Fmoc-HfLeu-OH see Supporting Information File 1. Peptide synthesis, purification and characterization Peptides were synthesized manually in a 0.05 mmol scale on a solid

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• )-CF3-threonine 14 was then purified by silica column chromatography and was obtained in 43% yield after three steps from 13 (Scheme 2). Classical peptide synthesis in solution was used to prepare pentapeptides 1a–4a (Scheme 3). Boc-L-Val-OH was activated by isobutylchloroformate (IBCF) and then coupled

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• alkene analogues (Table 4). Comparison between Phe-ψ[(Z)-CF=CH]-Gly and Phe-ψ[(E)-CF=CH]-Gly isosteres and their alkene analogues was also performed in an antagonist activity study towards GPR54. The fluorinated isosteres were incorporated into pentapeptides using Fmoc solid phase peptide synthesis (SPPS

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• and Discussion First we studied the preparation of simple Pro–Pro DKP as a model compound. The use of ball milling in peptide synthesis has drawn some attention in the recent years [20][21][22][23][24][25][26][27][28]. We took advantage of our extensive experience in peptide mechanosynthesis [20][23

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

• Ophélie Maurin,
• Pascal Verdié,
• Gilles Subra,
• Frédéric Lamaty,
• Jean Martinez and
• Thomas-Xavier Métro

Beilstein J. Org. Chem. 2017, 13, 2087–2093, doi:10.3762/bjoc.13.206

• Abstract While presenting particularly interesting advantages, peptide synthesis by ball-milling was never compared to the two traditional strategies, namely peptide syntheses in solution and on solid support (solid-phase peptide synthesis, SPPS). In this study, the challenging VVIA tetrapeptide was

• build more efficient and sustainable peptide syntheses in the near future. Keywords: ball-mill; green chemistry; mechanochemistry; peptide synthesis; SPPS; Introduction Peptides play a central role both in biological mechanisms and in therapeutic solutions of the future [1][2]. Pharmaceutical

• profiles (flammable, corrosive and/or toxic), and industrial manufacturers are making great efforts to reduce their use [8]. All these problematic chemicals have been widely used because they furnish liquid reaction mixtures perfectly adapted to the two prevalent peptide synthesis strategies utilized in

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• tRNA has been proposed recently [61]. With ribozymes involved in the catalysis of peptide-bond formation, and primal tRNAs as handles carrying amino acids used in the process, an alternative or complement to the swinging-arm peptide synthesis would have evolved in parallel, with RNA-dependent peptide

• complementarity rules (i.e., limiting the fuzzy complementarity rule used in specific peptide synthesis to standard A–U and G–C pairs). While this would perhaps also have been possible in a pure RNA environment, it was assisted by the same class of co-evolving molecules, the peptides that had favoured the

• formation of 3′,5′ over 2′,5′ bonds. Furthermore, peptides were also necessary for the machinery to help separating replicated strands, allowing for a further round of replication [63]. It can therefore be expected that RNA replicases evolved rapidly, in parallel with non-RNA-directed peptide synthesis. In

Novel β-cyclodextrin–eosin conjugates

• Gábor Benkovics,
• Damien Afonso,
• András Darcsi,
• Szabolcs Béni,
• Sabrina Conoci,
• Éva Fenyvesi,
• Lajos Szente,
• Milo Malanga and
• Salvatore Sortino

Beilstein J. Org. Chem. 2017, 13, 543–551, doi:10.3762/bjoc.13.52

• -yl)-4-methylmorpholinium chloride (DMTMMCl), a coupling reagent frequently used in peptide synthesis. Malanga et al. recently reported on the preparation of xanthene-dye-appended CDs with the most commonly used fluorescent probes rhodamine and fluorescein (Flu, 1). The conjugation of the 6-monoamino

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

• formed during peptide synthesis and purification were disrupted. As shown in Figure 1 the peptide KFM6 adopts a random structure upon dissolution in buffer and undergoes a time-resolved conformational transition to β-sheet-rich amyloid fibrils within 24 hours. The CD spectra (Figure 1a) show a typical

• those influences is a major challenge to use enzymatic phosphorylation as a tool to control the aggregation process and for the development of new functional biomaterials based on amyloid morphologies. Experimental Peptide synthesis, purification and characterization Peptides were synthesized manually