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

• fast renal clearance or low binding selectivity/affinity due to the unstable structure of the linear peptides, cyclic peptides have been introduced. An immense number of cyclic peptides have been synthesized [35][36][37] and many of them have displayed superior affinity and selectivity for the receptor

• than their parent linear counterparts [38]. Cyclic peptides are usually synthesized by reacting the N-terminus with the C-terminus or by exploiting specific functional groups of certain amino acids present in the sequence. A representative example is the sulfhydryl group of cysteine-containing peptides

• which may cyclize through the formation of intramolecular disulfide bonds [39]. The most commonly used linear peptides and cyclic peptides that can be delivered inside cancer cells via endocytosis and one that smuggles into glioma tissues via transcytosis (angiopep-2) are presented below: Arginine

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

• cyclic NGR peptide–Dau bioconjugates including chemostability, lysosomal degradation, cellular uptake studies and in vitro cytostatic/cytotoxic effect. Results and Discussion Synthesis of cyclic NGR–Dau conjugates The NGR cyclic peptides were prepared as shown in Figure 1. All derivatives were

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

• and the synthesis of peptides of biological relevance. Keywords: α-amino acid; catalysis; chiral pool; cross metathesis; cyclic peptides; Introduction α-Aminosuberic acid (Asu) is a component of apicidin F (1, Figure 1) belonging to an interesting class of cyclic tetrapeptides displaying

DMAP-assisted sulfonylation as an efficient step for the methylation of primary amine motifs on solid support

• Johnny N. Naoum,
• Koushik Chandra,
• Dorit Shemesh,
• R. Benny Gerber,
• Chaim Gilon and
• Mattan Hurevich

Beilstein J. Org. Chem. 2017, 13, 806–816, doi:10.3762/bjoc.13.81

• procedure on solid support [3][24][25]. These improvements enabled, for the first time, the synthesis of a combinatorial library of all possible N-methylated analogues of a given sequence [26]. These strategies have been used over two decades as standard procedures for N-methylations of linear and cyclic

• peptides, proteins, and small molecules on solid support, in addition to other organic compounds in solution phase [22][24][25][27]. We found that the introduction of a single methyl group to an amine adjacent to a hindered moiety using the state-of-the-art strategies is extremely challenging (Figure 1A

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• has occurred at an internal tryptophan residue of the precursor peptide. Kawaguchipeptin A Apart from the ComX pheromones, post-translational dimethylallylations of the tyrosine, threonine, serine, and tryptophan residues of cyclic peptides from cyanobacteria were reported [49][50][51]. The RiPPs

• derived from cyanobacteria, including dimethylallylated cyclic peptides, are called cyanobactins [2][37][38]. Although several cyanobactins exhibit significant biological activities, such as antibacterial and enzyme inhibitory properties, the actual biological role of prenylation in cyanobactins is still

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• concept and early studies showed that peptide bond formation could be achieved by modulating protease reaction conditions accordingly [106]. This has since been found to happen in the biosynthesis of cyclic RiPPs from a wide range of hosts, including cyclic peptides from both plants [105] and bacteria

• producing a cyclic octapeptide. A serine protease-like cyclase (PCY1) is also found in the biosynthesis of Caryophyllaceae-type cyclic peptides in Saponaria vaccaria [109]. This cyclase functions in an analogous way to PatG, although PCY1 has structural similarity to S9a family serine peptidases, whereas

• known peptide ligase or cyclase. The variety of unrelated cyclic peptides from phylogenetically distant plant families that are processed by AEP family proteins has led to the theory that this reflects evolutionary parallelism, where AEP functions as a constraining evolutionary channel due to its

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• to different cyclic peptides from Photorhabdus and Xenorhabdus species [42] and for activity testing of heterologously expressed SAM-epimerases from various bacteria [43]. In a follow-up study the recently discovered NRPS product kollosin A (16, Figure 4) was investigated. This pentadecapeptide is

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

• Jyotiprasad Mukherjee,
• Suman Sil and
• Shital Kumar Chattopadhyay

Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270

• -225497. Keywords: cross metathesis; cyclic peptides; diversity oriented synthesis; macrocycle; Introduction Diversity-oriented synthesis (DOS) has been established as an important paradigm in drug discovery [1][2][3][4][5][6][7]. Although the major focus is on the synthesis of small molecular libraries

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

• cyclization. All linear peptides were dissolved in CH2Cl2 (0.5 mM) and the pH was adjusted to 8 by addition of DIPEA. PyBOP (1.2 equiv) was added and the solution was stirred at room temperature for 1 h. Evaporation of the solvent and precipitation in diethyl ether afforded the cyclic peptides as white solids

• . General procedure for Boc deprotection. All cyclic peptides were dissolved in CH2Cl2 and then a solution at 40% of trifluoroacetic acid in CH2Cl2 with 2.5% of water as scavenger was added. The reaction was run until disappearance of stating material (1 h). Evaporation of the solvent and precipitation in

• diethyl ether afforded the cyclic peptides as white solids. Cyclopeptide 3. To a solution of partial protected cyclopeptide [Lys(Aloc)-Lys-Lys(Aloc)-Pro-Gly-Lys(Aloc)-Lys-Lys(Aloc)-Pro-Gly] (200 mg, 0.142 mmol) in dry DMF (10 mL) was added chloroacetic anhydride (100 mg, 0.304 mmol) and pH adjusted to 8

Molecular recognition of surface-immobilized carbohydrates by a synthetic lectin

• Melanie Rauschenberg,
• Eva-Corrina Fritz,
• Christian Schulz,
• Tobias Kaufmann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 1354–1364, doi:10.3762/bjoc.10.138

• biomimetic carbohydrate receptors [39]. To this end, we explored a dynamic combinatorial library of cyclic peptides to select receptors that are assembled from tripeptides under thermodynamic equilibrium. Amongst others, we identified a synthetic lectin (HisHis) that binds N-acetylneuraminic acid (NANA) [18

Homochiral BINOL-based macrocycles with π-electron-rich, electron-withdrawing or extended spacing units as receptors for C₆₀

• Marco Caricato,
• Silvia Díez González,
• Idoia Arandia Ariño and
• Dario Pasini

Beilstein J. Org. Chem. 2014, 10, 1308–1316, doi:10.3762/bjoc.10.132

• traditionally sought after for enhancing the recognition toward suitable guests [5][6][7][8][9][10], and for the self-assembly, of stable organic nanotubes from the macrocyclic structures as molecular building blocks [11]. Cyclic peptides [12][13][14], phenylacetylene macrocycles [15], amide-containing

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

• naturally occurring cyclic peptides containing a six-membered core ringsystem. Such DKPs were shown to possess several interesting medicinally relevant properties such as antifungal [133][134], antibacterial [135], and antitumor activity [136][137] but are also used to introduce for example a bitter taste

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• described in this review all comprise ring sizes of three to eight atoms; in contrast, macrocyclic structures have been little explored to date. It will be fascinating to learn whether similar effects operate in much larger ring sizes, for example in fluorinated analogues of cyclic peptides [76][77][78

New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei

• Annamaria Sinisi,
• Barbara Calcinai,
• Carlo Cerrano,
• Henny A. Dien,
• Angela Zampella,
• Claudio D’Amore,
• Barbara Renga,
• Stefano Fiorucci and
• Orazio Taglialatela-Scafati

Beilstein J. Org. Chem. 2013, 9, 1643–1651, doi:10.3762/bjoc.9.188

• hepatic carcinoma cell line. Keywords: antiproliferative activity; cyclic peptides; marine metabolites; theonellapeptolides; 2D NMR; Introduction Three decades of extensive chemical investigation [1] have clearly evidenced that marine sponges of the genus Theonella (Lithistida, Theonellidae) are

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

Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

• Julia Meier,
• Kristin Kassler,
• Heinrich Sticht and
• Jutta Eichler

Beilstein J. Org. Chem. 2012, 8, 1858–1866, doi:10.3762/bjoc.8.214

• importance of the salt bridge R59 for the stabilization of the interaction of the CDR2-like loop of CD4 with gp120, as CD4-M4 lacks this residue. Covalent stabilization of the spatial proximity between the N- and C-termini of peptides CD4-M1 and CD4-M4 through a disulfide bridge in the cyclic peptides CD4-M2

• affinity to gp120 between the cyclic peptides CD4-M2 and CD4-M5 on one hand, and their alanine substitution variants CD4-M3 and CD4-M6 on the other hand, could also be shown in a more quantitative fashion by dose-dependent binding of gp120 (Figure 3, left). In a separate binding assay, we addressed the

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

• containing an additional azide moiety, e.g., for ligation with click chemistry. Synthesis of cyclic peptides employing the oxidation-labile aryl hydrazide linker [11][24]. Functionalization of the cyclic β-tripeptide 4. Acknowledgements Financial support from the Deutsche Forschungsgemeinschaft (Research

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• case of cyclization using cyanuric chloride [25]. Unfortunately, the yield could not be improved above 17% in this case, so all further reactions were performed using the Thr(O-t-Bu) protected cyclic peptides 7 and 8. With cyclic peptides 7 and 8 in hand, we chose to attach the GHPD side chain to both

• compounds to enable the effect of peptide stereochemistry on the biological activity of the LI-F cyclic peptides to be assessed. Additionally, to investigate the effect of the 3-hydroxy group of the GHPD side chain on the biological activity of this class of cyclic peptide, we prepared the dehydroxy side

• significantly different peptide conformation [29]. Modelled structures of the side-chain-acylated cyclic peptides 24 and 25 obtained by using Monte Carlo conformational searches in Macromodel [30] suggest that these cyclic peptides adopt significantly different conformations with different arrangements of

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

• ; Introduction Diverse cyclic peptides, both natural and synthesized, are potent antibiotics [1][2][3]. Gramicidin S, vancomycine, bacitracin, polymixin B, colistin, valinomycin, actinomycin, and many more, have been tested and used clinically as antimicrobial and antifungal agents: It is believed that cyclic

• product purification [25][26][27][28][29]. According to the literature [30][31], most antimicrobial cyclic peptides are active in their cationic form. Cationic peptides are considered advantageous, because they adhere better to the outer anionic parts of phospholipid membranes. Although anionic peptides

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• tetramers of L-rhamno- and D-gulo-configured oxetane-SAAs 24 and 25 (Figure 12) have been synthesised by Fleet et al. [59] as mimics of naturally occurring cyclic peptides and cyclodextrins, although no further conformational and recognition studies on these compounds have currently been published. Urea