Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

• Martin C. N. Brauer,
• Ricardo A. W. Neves Filho,
• Bernhard Westermann,
• Ramona Heinke and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2015, 11, 25–30, doi:10.3762/bjoc.11.4

• increasing interest to synthesize dimerized peptidomimetics with pharmacological properties through a step-efficient protocol that allows rapid access to highly diverse dimer libraries, we set out to develop a strategy based on an U-4CR/Glaser-type homocoupling sequence [34]. In comparison to popular cross

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• electroorganic techniques and future directions. Keywords: anodic oxidation; electrochemistry; electroorganic, electrosynthesis, N-acyliminium ions; natural products; non-Kolbe oxidation; peptidomimetics; Shono oxidation; synthesis; Review N-Acyliminium ions are synthetically versatile N-Acyliminium ions [1][2

• into the synthesis of functionalised peptides and peptidomimetics using the anode oxidation strategy [91][92][93][94][95]. The anodic oxidation of pyrrolidine derivatives and silylated peptides afforded a variety of bicyclic lactam peptidomimetics and functionalised peptides (Scheme 22) [91][92][94

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• research on functionalized peptidomimetics, Moeller and co-workers found that the amide unit provides an excellent opportunity for oxidative modification of the peptide framework [50][51]. In order to construct constrained peptidomimetics, several electrochemical protocols for generation and cyclization of

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• -component reaction (U-4CR), can be adopted. The sequential combination of four species (amines, aldehydes, isocyanides and carboxylic acids) in a single-pot synthetic operation permits access to bisamide peptidomimetics through a highly electrophilic nitrilium intermediate [1][2][3][4]. Modification of the

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• MMP inhibitors by Hanessian and co-workers, trans- and cis-aziridines scaffolds were used as peptidomimetics to construct a series of hydroxamic acids analogs such as 17 (Scheme 17) [63]. While the trans-aziridines were prepared by conjugate addition of O-benzylhydroxylamine to α,β-unsaturated amides

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• subjected to post-Ugi transformations, paving the way to application as peptidomimetics. Keywords: isatin; multicomponent; oxindole; peptidomimetics; Ugi; Introduction Isatin and its derivatives have drawn considerable and renewed interest due to their peculiar chemistry and wide range of bioactivities

• interest was also the product 10, derived from a reaction of isocyanide 2d (Table 2, entry 7), since it can be easily converted into the correspondent primary amide derivative (vide infra). To explore potential applications of the Ugi reaction products in the field of peptidomimetics, we also tested the

• pharmacologically active peptidomimetics [41][42][43]. The reaction proceeded smoothly in methanol under reflux in the presence of excess TEA to give the product 18 by a regioselective six-exo-trig cyclization. Conclusion We have developed a novel approach to the synthesis of optically active 3,3-disubstituted 3

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

• produce these peptides in order to develop chemically engineered peptidomimetics or to uncover their distinct binding modes. Figure 4 illustrates possible strategies and Figure 5 feasible moieties for chemical modifications, which can be incorporated by semi-automated Fmoc/t-Bu-based SPPS. Amino acid

• generated more potent and stable peptidomimetics as compared to the wild types. Most steps within the synthesis of those analogs can be performed automatically by a peptide synthesizer, providing a fast and straightforward access to the peptides. SPPS can also be used to introduce specific tools into the

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• bioactive conformations [19]. Following the latter approach, Ib, shown in Figure 1, was designed as a novel potential ligand of the L-Glu receptors and building block for peptidomimetics. To the best of our knowledge, few structurally related azetidine derivatives 10a,b,11a,b and Ia [20][21][22], have been

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• attracted interest due to their use as structural elements as peptidomimetics [38][39], oligosaccharide mimetics [40][41] and induction of secondary structures [42][43][44][45][46]. Carbohydrate-derived β-amino acids used in this study were obtained by conjugate addition (Michael addition) of ammonia to a

Conformation of dehydropentapeptides containing four achiral amino acid residues – controlling the role of L-valine

• Michał Jewgiński,
• Joanna Krzciuk-Gula,
• Maciej Makowski,
• Rafał Latajka and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 660–666, doi:10.3762/bjoc.10.58

• this group of compounds. These peptidomimetics and natural peptides are characterized by a double bond between the Cα and Cβ atoms [2]. This modification entails a lot of structural consequences in the conformation of the peptides. The presence of a Cα–Cβ double bond together with two flanking peptide

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the

• peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both

• structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• (commercial trade names Halocur® (lactate salt) and Stenorol® (hydrobromide salt)) [22]. Other relevant examples are 3-hydroxypipecolic acids, which serve as (conformationally restricted) substitutes of proline and serine [23][24] and have been incorporated into diverse bioactive peptidomimetics [25][26], and

Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step

• James C. Anderson,
• Andreas S. Kalogirou,
• Michael J. Porter and
• Graham J. Tizzard

Beilstein J. Org. Chem. 2013, 9, 1737–1744, doi:10.3762/bjoc.9.200

• ]. They have been used to synthesise many nitrogen-containing functional groups including α-amino carbonyls [2][3], peptidomimetics [4], natural products [5][6][7][8][9][10] and many heterocyclic small molecules [11][12][13][14][15][16][17][18][19][20][21][22][23][24] of importance to drug discovery

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• /bjoc.9.24 Abstract A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH2 (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to

• establish that PLG binds to the D2 dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics

• containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• that characterizes the α-turn structure is confirmed by 1H NMR conformational studies. To the best of our knowledge, this scaffold represents one of the rare examples of a designed constrained α-turn mimic. Keywords: α-turn; conformational analysis; diketopiperazine; peptidomimetics; tetrahydro-β

• -HIV compounds [38]. Other examples of α-turn conformations are described in synthetic peptidomimetics [36][39][40][41][42]. Despite the growing interest in this kind of reverse turn and the need for all kinds of conformationally constrained mimics as tools for medicinal chemistry, the development of

• /EM conformational analysis for peptidomimetics 1a and 1b. The + symbol indicates the presence in the global minimum.

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• ][24][25], have emerged as powerful tools in the context of drug delivery [26][27][28][29], peptidomimetics and other biologically relevant applications [28][30][31][32] as well as materials science [33][34]. During the last decade the synthesis of polyamines and peptoids has been well established on

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

• innate immune system, the name “antimicrobial peptides” (abbreviated as AMPs) defines a larger group of peptides that also encompasses synthetic peptides, and peptidomimetics, for example. Among these, synthetic peptide-based antimicrobial agents are especially interesting because isolation and/or

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

• Workalemahu M. Berhanu,
• Mohamed A. Ibrahim,
• Girinath G. Pillai,
• Alexander A. Oliferenko,
• Levan Khelashvili,
• Farukh Jabeen,
• Bushra Mirza,
• Farzana Latif Ansari,
• Ihsan ul-Haq,
• Said A. El-Feky and
• Alan R. Katritzky

Beilstein J. Org. Chem. 2012, 8, 1146–1160, doi:10.3762/bjoc.8.128

• University, Islamabad 45320, Pakistan Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan Department of Chemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia 10.3762/bjoc.8.128 Abstract The chemical similarity of antibacterial cyclic peptides and peptidomimetics was

• . Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium. Keywords: antibacterial; cluster analysis; N-acylbenzotriazoles; peptidomimetics; similarity

• peptides are more stable to proteolysis due to the lack of free N- and C-termini, as well as reduced conformational freedom. Stability can also be achieved by modifying peptides into “peptidomimetics” that mimic and/or stabilize the secondary structure that modifies associated biological processes, thus

Antibiotic and cytotoxic peptides

• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1144–1145, doi:10.3762/bjoc.8.127

• in Medicinal Chemistry [2]. This Thematic Series on “Antibiotic and cytotoxic peptides” presents contributions from synthetic chemists active in the fields of peptides, peptidomimetics, drug design, and method development, in order to promote the research area further and to disseminate the

Parallel solid-phase synthesis of diaryltriazoles

• Matthias Wrobel,
• Jeffrey Aubé and
• Burkhard König

Beilstein J. Org. Chem. 2012, 8, 1027–1036, doi:10.3762/bjoc.8.115

• protein–protein interactions. Keywords: chemical diversity; Huisgen cycloaddition; library synthesis; peptidomimetics; solid phase synthesis; triazole; Introduction The α-helix was the first-described secondary structure of peptides discovered by Linus Pauling in 1951 [1]. With about 30% of the amino

• is another successful strategy [11]. Horwell pioneered this type of peptidomimetics and showed that 1,6-disubstituted indanes can imitate the helix residues i and i+1 [12][13]. Hamilton reported a 3,2′,2″-substituted terphenyl scaffold with a spatial orientation that mimics the i, i+3 and i+7

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

• the concept of rational drug design based on coiled-coil proteins [6]. In this context, the use of unnatural amino acids in peptidomimetics is advisable, to enhance enzymatic stability, limit conformational flexibility, and improve pharmacodynamics and bioavailability [7]. In order to manipulate helix

Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

• Elizabeth P. Jones,
• Peter Jones,
• Andrew J. P. White and
• Anthony G. M. Barrett

Beilstein J. Org. Chem. 2011, 7, 1570–1576, doi:10.3762/bjoc.7.185

• . Incorporation of such units into peptidomimetics, not only affects lipophilicity, but also the secondary structure and hence the conformational rigidity, which can increase the resistance to enzymatic degradation [15][16][17][18][19]. Such units are also found in biologically interesting natural products, such

Multicomponent synthesis of artificial nucleases and their RNase and DNase activity

• Anton V. Gulevich,
• Lyudmila S. Koroleva,
• Olga V. Morozova,
• Valentina N. Bakhvalova,
• Vladimir N. Silnikov and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2011, 7, 1135–1140, doi:10.3762/bjoc.7.131

• anticancer drugs [2][3] and new therapeutics against RNA-containing viruses. Recently, a number of synthetic RNA-cleaving molecules (artificial ribonucleases) had been developed and tested in vitro [4][5][6][7][8][9][10][11]. Among numerous artificial ribonucleases, peptidomimetics showed evident advantages

• due to their lower cytotoxicity and elevated potential penetration into living eukaryotic cells. Moreover, a few dipeptides [12] were shown to induce interferon production, thus providing antivirus defence. Therefore, the development of new peptidomimetics with ribonuclease activity is an important

• diamides. The benzyl groups can be easily removed from compounds 4 by the standard hydrogenolysis procedure. For example, using Pd/C as catalyst we obtained the target peptidomimetics 5 in up to 90% yield. Thus, we synthesized a number of racemic peptidomimetics 4 and 5, containing aliphatic or aromatic

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• cleavage; Ugi reaction; Introduction Fluorinated amino acids and pseudopeptides have increasingly attracted attention in recent years [1][2][3][4][5]. The selective incorporation of fluorine-containing groups, such as trifluoromethyl, difluoromethyl and difluoromethylene, into peptides or peptidomimetics

• reported of the preparation and bioassay of pseudopeptides and peptidomimetics bearing difluoromethyl groups. For example, compound I can act as bradykinin B1 antagonist or inverse agonist and can be used in the prevention of inflammation and pain [19]. Compound II is an inhibitor of microsomal

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• stereoselectivity. In conclusion, the methodology presented herein appears particularly well suited for the stereoselective preparation of libraries of peptidomimetics based on the tetrahydrobenzoxazepine ring. Although structures of general formula 6 are unprecedented, other tetrahydrobenzoxazepines have shown