Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• suitable for the coupling to peptides on resin, prepared by solid-phase peptide synthesis (SPPS) [35]. The detailed conditions for the amide-forming reaction were optimized using biscarboxylic acid-substituted C60 derivative 3 and a similar peptide with a primary amine derived from γ-aminobutyric acid

•  1). Results and Discussion Syntheses of C60–oligopeptides 5a–c The oligopeptides 2a–c were synthesized on resin using Fmoc-protected amino acids with a standard SPPS method (Figure 1a) [43]. A moderate loading (0.4 mmol⋅g−1) of the initial amino acid was used. After synthesizing the pentamer of Lys

• acid-substituted C60 derivative 3 and the peptides on resin 2a–c were performed by SPPS to provide the C60–oligopeptides on resin 4a–c (Figure 1a). Subsequently, the last step of the reaction – the cleavage of the C60–peptide conjugate from the resin and the simultaneous deprotection of the amino acid

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• attention is given to the strategies of mimics formation to demonstrate how biocatalysis provides an elegant link between chemistry and biology. Review Macrocyclic peptides Since first being reported in the 1960s [26], solid-phase peptide synthesis (SPPS) has been an invaluable tool for preparing numerous

• peptides and even small proteins. In the chemoenzymatic synthesis of macrocyclic peptides, SPPS strategies provide highly efficient routes to access linear precursors, accelerating the development of enzymatic macrocyclization. The tyrocidines Tyrocidine A (1), a cyclic decapeptide isolated from Bacillus

• -workers developed an elegant chemoenzymatic route in 2000 [36]. The synthesis commenced to construct linear decapeptide 2 by global SPPS method on 2-chlorotrityl resin. After coupling 2 with N-acetylcysteamine (NAC, 3), the mimic of peptide-S-PCP, peptide-SNAC 4 was prepared. When incubated with purified

Linker, loading, and reaction scale influence automated glycan assembly

• Marlene C. S. Dal Colle,
• Manuel G. Ricardo,
• Nives Hribernik,
• José Danglad-Flores,
• Peter H. Seeberger and
• Martina Delbianco

Beilstein J. Org. Chem. 2023, 19, 1015–1020, doi:10.3762/bjoc.19.77

• scale [19], and linkers [20][21] affect the overall yield of solid phase peptide synthesis (SPPS). In the past decades, several supports and linkers have been developed and commercialized for SPPS, enabling a wide range of applications. Solid supports are available with different linker loadings, with

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

• solid-phase peptide synthesis (SPPS) to generate the peptide segments ((G/GG/GGG)ffpy for 2a–h, 9, 10a,b, GGGFFpY for 3a,b, GGGffps for 4a,b, GGGffpS for 5a,b, aaaffpy for 6a–c, rffpy for 7, GGllllpy for 8a,b, GGGffy for 11a,b, aaaffy for 12a–c, NBD-ffky for 13, NBD-ffkpy for 14, GG(G) for 15a–c). Then

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• organoboron containing side chain in the i + 4-position. The peptides were synthesised on Rink amide resin by solid-phase peptide synthesis (SPPS) with Fmoc/t-Bu strategy followed by on-resin SMC. For the cross-coupling, a modified protocol by Planas and co-workers was used [78]. Pd2(dba)3 was employed as the

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• in Scheme 1, we initially tested Fmoc solid-phase peptide synthesis (SPPS) [13] to get 2-chlorotrityl resin-bound Pro1-(N-Me)-Phe2 dipeptide 2 under the conditions of HCTU and DIPEA. Unfortunately, the N-Me coupling proceeded in low yield (<10%). In order to improve the coupling yield of the hindered

• protected ʟ-Gln4, N-Me-ᴅ-Val5, ʟ-Ile6, N-Me- ʟ-Leu7, Ana8, and Hba9 units to give 9-mer peptide 9 using the standard SPPS procedure [13]. When ʟ-Ile6 and Ana8 were coupled, the reaction time was prolonged to 3 h in order to increase the yield. The peptide chain was then cleaved from resin by the solution of

• –90 vol % MeCN over 30 min, 90–90 vol % over 10 min, 90–10 vol % MeCN over 10 min) at a flow rate of 8 mL/min. Standard SPPS (solid-phase peptide synthesis) method: General procedures for coupling on resin: The loaded resin was shaken for 2 h at room temperature with a solution of the desired Fmoc-AA

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• safety [15][16][17]. Various effective receptor-binding peptides have been identified by the phage display technology [18]. The peptides can be readily prepared through solid-phase peptide synthesis (SPPS), a highly reproducible method with minimal side reactions. Many peptide–lipid conjugates

• structure [30]. These lipopeptides have a discrete molecular weight and are produced by Fmoc (fluorenylmethoxycarbonyl protecting group) SPPS, a procedure in which the peptide chain is assembled stepwise while attached to an insoluble resin support, which allows the easy removal of the byproducts at each

• . General procedure for the synthesis of perfluoroalkylated lipopeptides. All F-lipopeptides (SG)5-KSS-K(C2H4-CnF2n+1)2 with n = 6 (1), 7 (2), 8 (3) and hydrocarbon analog (SG)5-KSS-K(C10H21)2 were synthesized using an Fmoc solid-phase peptide synthesis (SPPS) method. Rink Amide AM resin (0.1 mmol) in a 10

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• -phase peptide synthesis (SPPS) methods (15 and 16, Figure 1). A second well-established methodology for the 19F isotopic labelling of protein and peptides involves the post-translational chemical conjugation of an 19F probe to specific amino acids present within the protein, typically cysteine and

• combined with the aforementioned chemical approaches based on cysteine and lysine modification. It is worth noting that for small proteins and peptides the chemical incorporation of the desired fluorinated amino acids using SPPS protocols still remains the method of choice, as it enables the site-specific

• introduction of the 19F NMR probe. In addition, SPPS offers a powerful technique to access uniquely labelled peptides and proteins when combined with new strategies for peptide stapling and tagging using perfluoroaromatic reagents. Perfluorophenyl, perfluoropyridyl and perfluoropyridazinyl labelled peptides

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• , HOAt, NMM, DMF, 0 °C to rt, 15 h, 93%; iv) SPPS using HBTU, HOBt, DIPEA for coupling (HATU for BTA coupling), 20 vol % piperidine in DMF for Fmoc cleavage, DCM/TFA/TIS 20:20:1 (v/v/v) for final cleavage, 68%; v) azidoacetic acid NHS ester, NMM, DMF, rt, 4 h, 81%; vi) 4, PyBOP, HOAt, NMM, DMF, 0 °C to

Enzyme-instructed morphological transition of the supramolecular assemblies of branched peptides

• Dongsik Yang,
• Hongjian He and
• Bing Xu

Beilstein J. Org. Chem. 2020, 16, 2709–2718, doi:10.3762/bjoc.16.221

• synthesis (SPPS) [47] to produce the peptides shown in Scheme 1. We first synthesized the peptide segments (i.e., Fmoc-DEDDDLLIG (1a) and acetyl-DEDDDLLIG (2a)). We kept the tert-butyl protecting groups of aspartic acid for the coupling reaction with Nap-ffky. We used 2,2,2-trifluoroethanol (TFE) in

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• . Microwave-assisted SPPS was carried out using a CEM Discover system. 1H and 13C NMR spectra were recorded on a DRX 500 MHz Bruker spectrometer at ambient temperature. Chemical shifts (δ) are expressed in parts per million and J values in hertz. The following abbreviations were used for peak multiplicities

A dynamic combinatorial library for biomimetic recognition of dipeptides in water

• Florian Klepel and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2020, 16, 1588–1595, doi:10.3762/bjoc.16.131

• CXC peptide building block design (single-letter code) were the terminal amino acids are cysteine (C) and the X can be any amino acid (Scheme 1a). This allows for rapid synthesis of various new building bocks by standard Fmoc based SPPS using Trt protecting groups for cysteine, which are subsequently

• SPPS. Thus one cysteine moiety is left deprotected and can be addressed selectively either by dimerization with another CFC(Acm) or with inversely substituted tripeptide (C(Acm)FC). These linear peptide dimers were subsequently cyclized by oxidative cleavage of the Acm groups to give a(CFC)2 and p(CFC

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

• azidochlorination [25]. Glycosylated building blocks, containing ʟ- or ᴅ-Thr were synthesized (Figure 1) over three steps [26]. The glycosylated building blocks were used in SPPS of model tri- and pentapeptides. The N-terminal end of the products was acetylated and the carboxy terminus was in a form of N

• the resin linker in an efficient four-step procedure compatible with Fmoc-based SPPS. In the first step the Fmoc group was cleaved by treatment with 20% piperidine in DMF giving the free amino function on the resin linker. Then the resin was washed with DCM, DMF and NMP. In the next step the free

• (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

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

• side chain protecting groups such as Trt (chlorotrityl), Mtt (4-methyltrityl), Mmt (4-methoxytrityl) for the synthesis of targeted fluorescent bioconjugates. The methodology was further extended to synthesize FR targeted fluorescent chelating conjugate 17 as shown in Scheme 4. Using standard Fmoc SPPS

• peptide synthesis (SPPS) as well as in chemical synthesis were purchased from Iris Biotech GmbH, Sigma-Aldrich, Merck and Spectrochem. Dry solvents were prepared by using drying agents and following usual methods. Peptide syntheses were carried out in sintered glass peptide vessels (Chemglass) by standard

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

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

• . 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

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

• conjugates with two different drug molecules or Lys(Ac) in position 4, orthogonal protecting schemes were applied during the SPPS. For the preparation of the disulfide dimers, an additional Cys was attached to the ε-amino group of 8Lys of the GnRH-III derivatives. First, Dau was linked to the aminooxyacetyl

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

• synthesized using a combination of standard Fmoc/t-Bu solid-phase peptide synthesis (SPPS) on a Syro I peptide synthesizer (MultiSynTech, Bochum, Germany) and manual coupling protocols according to previous works [17][19][20]. Peptides were generated on a Rink amide resin (loading 0.48 mmol/g) yielding C

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

• peptide synthesis and cyclic peptide synthesis. Results and Discussion At the beginning of our study, we tried to utilize the system of FPID/(4-MeOC6H4)3P in the solid-phase peptide synthesis (SPPS). SPPS has been widely employed in peptide synthesis since its first report by Merrifield in 1963 [30][31

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

• synthesized by SPPS on a Rink-Amide MBHA Resin, using Fmoc/t-Bu strategy. The anticancer drug daunomycin was conjugated to the Aoa-GFLGK spacer via oxime linkage [17]. This spacer is degraded by lysosomal enzymes ensuring the release of the Dau=Aoa-Gly-OH as the smallest bioactive metabolite in lysosomes [19

• [NleNGRE]-GG)-NH2 conjugate is more suitable for drug targeting with dual acting propensity than our control lead compound. Experimental Synthesis of the novel peptide–drug conjugates Linear precursor peptides were prepared on Rink-Amide MBHA resin by SPPS. Standard Fmoc protected amino acids (Iris Biotech

• GmbH, Marktredwitz, Germany) were used for the synthesis except Fmoc-Lys(Mtt)-OH that was applied for the development of branching in the peptide. The protocol of the SPPS was similarly as described in [17] as follows: (i) DMF washing (4 × 0.5 min), (ii) Fmoc deprotection with 2% DBU, 2% piperidine

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

• 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

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

• isomerization or epimerization, cyclic pseudopeptides using Fmoc SPPS [48][50]. Biological studies were conducted on monofluoroalkene-containing analogues of FC131, which is a known antagonist of the chemokine receptor CXCR4. The latter has implications in cancer metastasis and HIV 1 infection. Anti-HIV 1

• pentapeptide Leu-enkephaline, which can have analgesic properties when bounded to the DOPr receptor [36]. In order to study some derivative of the peptide, Fmoc-Gly-ψ[(Z-CF=CH]-Phe was synthesized (see Scheme 9). Using Fmoc SPPS, the fluorinated mutant was incorporated in the sequence of the Leu-enkephaline to

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

• research laboratories and for industrial production: synthesis in solution and synthesis on a solid support (also known as solid-phase peptide synthesis, SPPS). Indeed, liquid reaction mixtures enable efficient agitation when using a conventional batch reactor equipped with either magnetic stirring bar or

A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• of the GHPD side chain building block. Thus, Cudic’s SPPS approach should be combined with the advantages of the late stage coupling employed by Jolliffe. Synthesis The C13-fragment was prepared starting from erucamide (6) in three simple operations. Reduction of the amide with lithium aluminium

• alcohol 12 was subjected to ozonolysis and Pinnick oxidation to furnish the protected GHPD acid 3 in an overall yield of 14.3%. The peptide core was synthesized manually according to a standard SPPS Fmoc protocol using HATU and NMM in NMP [16]. For protection of the threonine unit, it was converted into a

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• et al. [47]. These syntheses substituted the enduracididine residue for the more readily available L-arginine. The total synthesis of the full teixobactin structure was completed in 2016 by Payne et al. [72] using Fmoc solid-phase peptide synthesis (SPPS). The key to the synthesis was access to the

• Fmoc-D-Thr(TES)-OH on HMPB-NovaPEG resin. Successive couplings afforded peptide 104 (Scheme 23). Esterification with Alloc-Ile-OH and extension of the linear chain using conventional Fmoc SPPS afforded ester-peptide 105. Deprotection of the N-alloc group and coupling of the key L-allo-enduracididine