Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• , Zaporizhzhya National University, Zhukovsky str., 66, Zaporizhzhya, 69600, Ukraine 10.3762/bjoc.19.53 Abstract Peptidomimetics with a substituted imidazo[1,2-a]pyridine fragment were synthesized by a tandem of Groebke–Blackburn–Bienaymé and Ugi reactions. The target products contain substituted imidazo[1,2-a

• attention to another isocyanide multicomponent reaction – the Ugi reaction [21], which is one of the most important methods for the synthesis not only of peptidomimetics but also of other types of complex organic compounds. The presence of several diversity points and modification of starting components for

• (Scheme 2). It is obvious that the exploration of the possibility to create hybrid molecules by combining GBB-3CR and Ugi is successful, so one of the promising areas is to increase the diversity of relevant compounds using substituted aminopyridines in GBB-3CR and the synthesis of new peptidomimetics

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

• Maxime Pypec,
• Laurent Jouffret,
• Claude Taillefumier and
• Olivier Roy

Beilstein J. Org. Chem. 2022, 18, 845–854, doi:10.3762/bjoc.18.85

• ]. Beyond their resemblance to peptides, the obvious interest in this family of peptidomimetics arises from their ease of synthesis by the modular submonomer protocol [9] which enables the incorporation of numerous primary amine synthons in a sequence-controlled manner [10], and application of solid

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• commonly utilized as key intermediates for the synthesis of boron-containing peptidomimetics, which have been demonstrated to be efficient covalent ligands and valuable protease inhibitors endowed with various biological activities [5][6]. Going on with our interest in the synthesis of 3,3-disubstituted

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• reaction selectivity. The new procedure proceeds in a higher yield than previously obtained and may potentially offer benefits in large-scale manufacture of integrin inhibitors and other arginine peptidomimetics. The Arg–Gly–Asp tripeptide sequence and examples of tetrahydro-1,8-naphthyridine-containing

Synthesis of new asparagine-based glycopeptides for future scanning tunneling microscopy investigations

• Laura Sršan and
• Thomas Ziegler

Beilstein J. Org. Chem. 2020, 16, 888–894, doi:10.3762/bjoc.16.80

• Laura Srsan Thomas Ziegler Institute of Organic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany 10.3762/bjoc.16.80 Abstract For investigations on the biological functions of oligosaccharides and peptidomimetics, new asparagine-based mono- and disaccharides

• cell surfaces for future investigations by combined preparative mass spectroscopy and scanning tunneling microscopy (STM) using soft-landing electrospray beam deposition (ES-IBD), on metal surfaces. Keywords: amino acids; asparagine; carbohydrates; glycopeptides; peptidomimetics; Introduction

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

• Sergii Afonin,
• Oleg Babii,
• Aline Reuter,
• Volker Middel,
• Masanari Takamiya,
• Uwe Strähle,
• Igor V. Komarov and
• Anne S. Ulrich

Beilstein J. Org. Chem. 2020, 16, 39–49, doi:10.3762/bjoc.16.6

• such comparisons are known for peptides or peptidomimetics. When plotting the D. rerio embryotoxicity LD50 values of the ring-open (activated, ON) photoforms against the in vitro HeLa cytotoxicity indicators, namely against IC50 [30] of the ring-closed (deactivated, OFF) photoforms (Figure 5A), the

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

• structurally related to these natural peptidomimetics has been used as a promising strategy for the attenuation of bacterial virulence in strains of S. aureus [12][13][14][15]. Herein, we report the synthesis of new sulfide-based cyclic peptidomimetics through the allylic nucleophilic substitution (SN2’) of

• , this is the first report on the participation of MBH residues as electrophilic sites to allow an SN2’-based macrocyclization of peptidomimetics [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Two of these new compounds were able to interfere with the hemolytic activity of S. aureus, and

• repetitive Fmoc-amino acid couplings yielding the linear resin-bound tetrapeptides 5 (Scheme 3) [37][38]. The MBH acids 3 were coupled to the free amine at the N-terminal of 5 to afford the resin-bound linear peptidomimetics 6, which subsequently had the hydroxy group of the MBH residue acylated with acetic

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• CXCR3 agonists are scarce and are mostly limited to peptidomimetics [25], which makes our published biaryl series a notable exception [24]. The general scaffold of these biaryl ligands consists of a polycycloaliphatic anchor and a biaryl moiety both linked to an ammonium ion. Depending on the

Sugar-derived oxazolone pseudotetrapeptide as γ-turn inducer and anion-selective transporter

• Sachin S. Burade,
• Sushil V. Pawar,
• Tanmoy Saha,
• Navanath Kumbhar,
• Amol S. Kotmale,
• Manzoor Ahmad,
• Pinaki Talukdar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2019, 15, 2419–2427, doi:10.3762/bjoc.15.234

• transporter for which an anion–anion antiport mechanism was established. Keywords: ion transport; oxazolone; peptidomimetics; pseudo-peptides; sugar amino acid; Introduction Tetrasubstituted α-amino acid (TAA)-derived peptidomimetics offer well-defined turn structures due to the presence of a

• conformation [5]. Amongst these, the use of sugar-derived TAAs in peptidomimetics is less explored. The linear tri-/tetrapeptides and spiro-peptides at the anomeric position of mannofructose are known [6][7][8]. Stick and co-workers have reported the synthesis of tetrasubstituted sugar furanoid amino acid

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• the basis of a large group of reactions in organic chemistry, especially in isocyanide-based multicomponent reactions (IMCRs) [2][3], such as the Passerini and Ugi reactions, which are reactions that have been widely used in the synthesis of peptides, peptidomimetics and heterocycles [4][5][6][7][8

• -aminomethyltetrazoles 18 in up to 99% yield. Another recent study carried out the synthesis of tetrazole peptidomimetics by the direct use of unprotected amino acids in two consecutive Ugi-type reactions [24]. Acid-tetrazole compounds 19 were obtained using C,N-unprotected amino acids in an Ugi-tetrazole reaction with

• isocyanides to obtain six tetrazole peptidomimetics (20a–f). Highly complex molecules were easily obtained in only two steps (sequential Ugi-tetrazole/Ugi-reaction) without the need for amino acid protection/deprotection reactions. A remarkable result was described by Orru and co-workers who used two

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• peptidomimetics with potential pharmaceutical applications. Therefore, the development of innovative Ugi reactions is crucial for the synthesis of novel chemical libraries for various purposes [12]. In recent years, one of the modifications for Ugi reactions is the introduction of bifunctional substrates into the

• -component reaction. The main advantage of this paper refers to the application of three amino acid-based isocyanides in the reaction with levulinic acid as a bifunctional substrate and amines which led to the formation of novel peptidomimetics with potential biological activities. In addition, the presence

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• antitumor peptidomimetics (Scheme 16) [53]. The convergent approach employs three different isocyanide-MCRs, efficiently prepares the building blocks and combines them, intercalating protecting group cleavages. Conclusion The MMCRs approach represents the most efficient way to build chemical complexity and

• . Stepwise access to 6-aminopenicillanic acid derivative through an Asinger, deprotection, Joullié approach. A triple MCR-deprotection approach affording anticancer peptidomimetics. Acknowledgements Financial support from the Ministerio de Economía y Competitividad-Spain (MINECO, CTQ2015-67870-P) and

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• 1,4-disubstituted triazoles 8 through click reaction between 2-azidomethyl-4,5-diaryloxazoles and alkynes in the presence of a copper(I) catalyst (Scheme 2). The authors were able to synthesize an array of small-molecule peptidomimetics that inhibited Porphyromonas gingivalis biofilm formation [34

• azides 1a–c. Yields refer to isolated yields. Synthesis of oxazoles 4 by addition of acyl chlorides to azirines 2, as described by Hassner et al. [28][29]. Preparation of 2-functionalized oxazoles 7 from 2-(chloromethyl)oxazoles 6 and their application to the synthesis of peptidomimetics 8. Integrated

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• , αVβ6, and α5β1. These data indicate that in this case the cyclo[DKP-isoDGR]-α-amanitin conjugates are possibly internalized by a process mediated by integrins different from αVβ3 (e.g., αVβ5). Keywords: antitumor agents; cancer; drug delivery; integrins; peptidomimetics; Introduction α-Amanitin is a

• synthetic peptides or peptidomimetics containing these sequences have been prepared and show low nanomolar IC50 values for integrin αVβ3 binding [21][22][23][24][25][26][27]. A number of cyclic RGD and isoDGR ligands containing a bifunctional diketopiperazine (DKP) scaffold have been developed by the

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

• /peptidomimetics that displayed inhibitory activity at high ratios show greater aggregation inhibitory activity at 1:1 ratio or even less, when they are incorporated in such designed structures [15][39][40][41]. A) Natural threonine and its trifluoromethyl analogues sawhorse projections. B) Structure of Boc

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• presents several advantages. For instance, hydrazinopeptides comprise a class of peptidomimetics with promising biological and conformational activities [18][19][20][21]. It is worth mentioning that in such compounds the so-called "hydrazino-turns" are formed through intramolecular hydrogen bonding between

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

• order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral

• groups is accessible for the use as precursors of peptidomimetics. Keywords: amino acid analogous side chains; desilylation; Ellman’s chiral sulfinamide; intramolecular Huisgen reaction; peptidomimetics; propargylamines; rearrangement to α,β-unsaturated imines; Introduction Terminal alkynes display an

• ], gold-catalyzed azetidin-3-one formation [16], as well as various transition metal-mediated additions and cross-coupling reactions [17] represent further important reactions of propargylamines, providing the potential to form innovative peptidomimetics (Figure 2). Our attention has been focused on the

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

• feature, used for the preparation of biologically active peptides and peptidomimetics [7], for applications in organocatalysis [8][9][10], and for the preparation of novel materials [11][12]. An interesting sub-family of these compounds are DKPs derived from the amino acid proline and its analogues, which

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

• of peptidomimetics. A cross-metathesis reaction has been utilized to create the diversification on the template 11 in order to obtain orthogonally protected Asu derivatives. Moreover, the Asu derivative 15a has been demonstrated to be useful in the preparation of a plethora of HDAC inhibitors [34

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• primary amines that allowed using it as an amine component in Ugi-4CR. Particularly, its reaction with aromatic aldehydes 1a–h, phenylpropiolic acid (8) and tert-butylisocyanide (3a) gave peptidomimetics 9 under stirring the starting reagents in MeOH at room temperature for 24 h. In the presence of strong

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• for the synthesis of acylhydrazino-peptomers, a new class of peptidomimetics. The key idea in this approach is based on a simple route using a one-pot hydrazino-Ugi four-component reaction followed by a hydrazinolysis or hydrolysis reaction and subsequent hydrazino-Ugi reaction or classical Ugi

• peptidomimetics with potential biological activity. Keywords: acylhydrazino-peptomers; consecutive Ugi reactions; peptide-peptoid hybrid; peptomer; Introduction In the last decades, increasing efforts have been extensively carried out to improve the pharmacological properties of natural peptides by structural

• modification of the amino acids [1][2][3][4][5][6][7][8]. These modifications allowed the obtention of molecules that mimic the properties of peptides (peptidomimetics) but usually exhibit greater proteolytic stability, increased cellular permeabilities and avoid stereochemical constraints. Figure 1 represents

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• peptidomimetics possessing phosphonate groups by MCR-based strategies would significantly extend the synthetic potential of MCRs towards heterocyclic phosphonates. The Biginelli condensation. The Biginelli reaction of β-ketophosphonates catalyzed by ytterbium triflate. Trimethylchlorosilane-mediated Biginelli

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers

• , allowing the introduction of five diversity inputs. Keywords: aminoalcohols; isocyanides; multicomponent reactions; peptidomimetics; Ugi reaction; Findings Isocyanide-based multicomponent reactions [1][2][3], such as the Ugi reaction, were demonstrated to be very useful in the rapid assembly of complex

• poor stereochemical control that is typically achieved [8][9], which hampers its utilization in the diversity-oriented or target-oriented synthesis of complex chiral peptidomimetics. No efficient asymmetric catalytic classic Ugi reaction has been reported to date (whereas some success was obtained on

Synthesis of constrained analogues of tryptophan

• Elisabetta Rossi,
• Valentina Pirovano,
• Marco Negrato,
• Giorgio Abbiati and
• Monica Dell’Acqua

Beilstein J. Org. Chem. 2015, 11, 1997–2006, doi:10.3762/bjoc.11.216

• products and biochemical studies. In recent years, both pharmaceutical companies and academics became interested in the design and synthesis of peptidomimetics and peptide analogues as new therapeutic drugs [2][3]. Medicinal chemistry progress in these fields was probably inspired by the biochemical

• interactions and reduced oral absorption that prevent their use in therapy [4]. On the other hand, peptidomimetics offer the advantage of nearly countless manipulations in order to control the biological functions, stability, potency, and ADME parameters [5]. In particular, the inclusion of the amino acidic

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• , peptidomimetics of the α5β1 antagonist and the αvβ3 antagonist were synthesized, respectively (Figure 3). Both peptidomimetics can selectively mediate cell adhesion by binding with the relative single integrin subtype without losing activity, while avoiding unspecific adhesion and integrin binding. This

• -selective (right) peptidomimetics. Reprinted with permission from [22]. Copyright 2013 Wiley. When the distance between two neighboring integrin ligands is <70 nm, the focal adhesions and contractile actin cytoskeletal stress fibres allow cell spreading (a). When the distance is >70 nm, the formation of