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

• units have been employed in developing bicycle-based peptidomimetics, the thiomethylene unit is quite attractive as the synthesis into such systems is simplified, because the amino acid cysteine can be used. This bicyclic constraint was initially developed by Nagai and Sato [41]. In this constrained

• accomplished through the condensation of α-alkylaldehyde proline derivatives 34a–c with either D-cysteine or D-homocysteine derivatives to give diastereoisomeric mixtures of thiazolidines 35, 37 and 38 and thiazines 36, respectively (Scheme 2). Formation of the lactam ring from the thiazine and thiazolidines

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• , 1700 4th Street, San Francisco, CA, 94158, USA Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio de Janeiro, RJ, Brazil 21040-362 10.3762/bjoc.9.3 Abstract Inhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the

• investigated are cruzain [7][8][9][10], the major cysteine protease active in the parasite, and T. cruzi CYP51 (TcCYP51), a 14-α-demethylase enzyme of the cytochrome P450 family required for ergosterol biosynthesis [11][12][13][14]. TcCYP51 is analogous to the fungal enzyme targeted by the azole class of

• intracellular replication and differentiation of the T. cruzi parasite [17]. A variety of small-molecule cruzain inhibitors have been described, the majority of which act irreversibly by reaction with the catalytic cysteine in the enzyme active site [18][19][20][21][22][23][24][25][26][27]. One of the earliest

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• led to the fluorenylmethyl-protected thioether 8 in high yield. The suggested mechanism for this reaction comprises the addition of the cysteine thiolate on the exocyclic double bond of dibenzofulvene, which is formed during Fmoc deprotection. The influence of base concentration on this

• transprotection reaction was studied. Keywords: Fmoc protecting group; glycoamino acids; N-Fmoc→S-Fm transprotection; protecting groups; Introduction In the course of our work on the synthesis of glycoamino acids, we have recently used L-cysteine as a scaffold for the synthesis of various glycoclusters [1][2][3

• oxidiation of the cysteine moiety into the respective cystine form. Indeed, preparation of glycoamino acid derivatives such as 3-dimer, an oxidized cysteine, or cystine derivative, is facile and can be realized via different synthetic routes. However, as we employed the fluorenylmethoxycarbonyl (Fmoc

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• protected as tert-butyl ethers (tyrosine), tert-butyloxycarbonyl derivatives (lysine), trityl derivatives (cysteine, glutamine), and as (2,2,4,6,7-pentamethyl)dihydrobenzofuran-5-sulfonyl derivative (arginine). Coupling was performed by using a 4-fold excess of each of the protected amino acids and the

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

• P48 (10.6 Å), we also generated peptides in which this proximity is covalently stabilized. This was achieved by means of a disulfide bridge between cysteine residues, which were introduced either by replacing S23 and D63 with cysteine (CD4-M2 and CD4-M3), or by being added to either side of the CD4

• additional cysteine residues in CD4-M5, CD4-M6 and CD4-M7, was separated from the CD4 sequences by the spacer amino acids ε-aminohexanoic acid (X) and β-alanine (B). All peptides were generated through solid-phase synthesis and purified by preparative HPLC (Figure 2 and Experimental section). Peptide binding

• for the CD4–gp120 complex (black). (A) Root-mean-square deviation of the peptides and CD4 over simulation time. (B) Root-mean-square fluctuation of individual residues measured for backbone atoms averaged over time. Residues replaced by cysteine in CD4-M2 are indicated in bold face. Secondary

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

• enantiomeric recognition [22][23]. Incorporation of amino acids in abiotic anion receptors can lead to systems that mimic the anion coordination properties of anion-binding proteins [24]. Introduction of cysteine subunits into a macrocycle facilitates receptor synthesis and allows control of the relative

• direction of the two chains attached to the cysteine residue. For example, one of the early cysteine-containing macrocycles was designed to mimic the cation binding ability of valinomycin [24]. Numerous literature approaches to the synthesis of 17-, 18- and 24-membered rings utilize: (i) acyl chlorides, (ii

• cysteine in aqueous acetonitrile at 20 °C over 12 h to give bis(S-acylcysteine) 36 in 64% yield. Compound 36 was then treated with 1 equiv of 35a–c to synthesize cyclic enantiopure peptidomimetic products 37a–c in 81–82% yield (Scheme 2, see Supporting Information File 1 for experimental details). In a

Control over molecular motion using the cis–trans photoisomerization of the azo group

• Estíbaliz Merino and
• María Ribagorda

Beilstein J. Org. Chem. 2012, 8, 1071–1090, doi:10.3762/bjoc.8.119

• , azobenzene and glutamate derivative (MAG) was used as a photochromic agonist of an ionotropic glutamate receptor (iGluR) (Figure 5a) [89][90][91]. The chromophore consists of a terminal maleimide unit, which is associated covalently to the protein via a cysteine residue, a central azobenzene unit and a

• described by Woolley et al. [92][93]. They introduced an azobenzene moiety in a polypeptide to control the α-helical conformation and to have a synthetic tool that allows photomodulation of the very important conformation–interaction relationship in biological recognition. Peptides with pairs of cysteine

• residues were intramolecularly cross-linked with thiol reactive azobenzene-based photoswitches. Photoisomerization of the azobenzene changes the conformation of the peptide depending on the location of the cysteine. When the azo group of polypeptide 2 is in its trans form, it retains its affinity for DNA

Multistep organic synthesis of modular photosystems

• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2012, 8, 897–904, doi:10.3762/bjoc.8.102

• 21. After chemoselective, acid-catalyzed deprotection, the liberated amines were coupled with the Boc-protected cysteine tert-butyl disulfide 22. The obtained amide 23 was treated with TFA for Boc removal and coupled with the geminal diphosphonate foot 7. Deprotection of both hydrazides and

Building photoswitchable 3,4'-AMPB peptides: Probing chemical ligation methods with reducible azobenzene thioesters

• Gehad Zeyat and
• Karola Rück-Braun

Beilstein J. Org. Chem. 2012, 8, 890–896, doi:10.3762/bjoc.8.101

• Gehad Zeyat Karola Ruck-Braun Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany 10.3762/bjoc.8.101 Abstract Photoswitchable peptides were synthesized by using cysteine- and auxiliary-based native chemical ligation reactions. For this purpose, the

• -terminal thioester peptide and either an N-terminal cysteine peptide or Nα-auxiliary-capped peptides. However, for elucidating the complex redox chemistry of the two azobenzene building blocks under the reducing conditions of ligation methods, we solely applied the Boc-protected azobenzene ω-amino acid

• thioesters 1b and 2b instead of a C-terminal thioester peptide. We explored the conventional cysteine-based NCL with Cys-peptide 3, and also screened the application of the TFA-cleavable 4,5,6-trimethoxy-2-mercaptobenzyl (Tmb) and 1-(2,4-dimethoxyphenyl)-2-mercaptoethyl auxiliaries by using peptides 4 and 5

Intramolecular bridges formed by photoswitchable click amino acids

• Christian Hoppmann,
• Ronald Kühne and
• Michael Beyermann

Beilstein J. Org. Chem. 2012, 8, 884–889, doi:10.3762/bjoc.8.100

• a photoswitchable unit elongated with a functional group that allows for a specific click reaction, such as an alkene that can react with the thiol group of a cysteine residue. An intramolecular click reaction results in the formation of a photoswitchable bridge, which can be used for controlling

• conformational domains in peptides and proteins. The ability to control conformations as well as the efficiency of the intramolecular bridging depends on the length of the PSCaa side chain and the distance to the cysteine residue to be clicked with. On comparing i,i+4 and i,i+7 spacings of PSCaa and cysteine in

• presence of glutathione as an additional thiol the click reaction of the PSCaa occurs intramolecularly with the cysteine rather than with the glutathione, indicating that the click reaction may be used even under reducing conditions occurring in living cells. Keywords: azobenzene; helical conformation

High-affinity multivalent wheat germ agglutinin ligands by one-pot click reaction

• Henning S. G. Beckmann,
• Heiko M. Möller and
• Valentin Wittmann

Beilstein J. Org. Chem. 2012, 8, 819–826, doi:10.3762/bjoc.8.91

• ][29][30][31][32][33][34][35][36] or from screening of combinatorial libraries [37][38] have been reported. WGA is a 36 kDa plant lectin composed of two identical glycine- and cysteine-rich subunits [39] and is enriched in the seeds of Triticum vulgaris. It is specific for terminal N-acetylneuraminic

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• cysteine, followed by a S→N acyl shift. The development of a variant of NCL, namely expressed protein ligation (EPL), has further made it possible to efficiently prepare large proteins without the size limitations set by ordinary peptide synthesis [45]. Bertozzi and co-workers introduced the NCL and EPL

• Fmoc-SPPS followed by sequential NCL [51]. The N-glycopeptide fragment RNase 26–39 (17) was prepared with a thioester in the C-terminal and a thiazolidine protected cysteine at the N-terminus. The chemical ligation was performed by coupling of the N-glycopeptide thioester RNase 26–39 (17) and the

• expressed protein fragment 40–124 (18) containing a N-terminal cysteine, employing thiophenol and tris(2-carboxyethyl)phosphine (TCEP). The obtained RNase fragment 26–124 (19) was then treated with N-methoxyamine (0.2 M, pH 3–4, 4 h) to remove the protecting group on the N-terminal cysteine. Ligation of the

Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663

• Orwah Saleh,
• Katrin Flinspach,
• Lucia Westrich,
• Andreas Kulik,
• Bertolt Gust,
• Hans-Peter Fiedler and
• Lutz Heide

Beilstein J. Org. Chem. 2012, 8, 501–513, doi:10.3762/bjoc.8.57

• as = +16.8 (c = 0.33, MeOH). Endophenazine E is a new natural product. The conjugation of a phenazine to N-acetylcysteine has been described previously [17]. In that case, conjugation occurred through the thiol group of cysteine and led to the loss of the antibacterial activity of the phenazine. A

Intramolecular carbenoid ylide forming reactions of 2-diazo-3-keto-4-phthalimidocarboxylic esters derived from methionine and cysteine

• Marc Enßle,
• Stefan Buck,
• Roland Werz and
• Gerhard Maas

Beilstein J. Org. Chem. 2012, 8, 433–440, doi:10.3762/bjoc.8.49

• Synthesis of diazoesters The 2-diazo-3-oxo-4-phthalimidocarboxylic esters 8a–c were prepared from L-methionine (5a), S-benzyl-L-cysteine (5b) and S-allyl-L-cysteine (5c), respectively, in a three-step sequence (Scheme 3) applied by us previously for other α-aminoacids [18]. Acids 5a–c were converted into

• rotation value for N,N-phthaloyl-L-methionine (6a), but racemisation occurred to a significant extent in the case of S-benzyl-N,N-phthaloyl-L-cysteine (6b) (Supporting Information File 1). Practically complete racemisation took place during conversion of N-protected aminoacids 6a–c to the β-ketoesters 7a–c

• ] cycloaddition with the dipolarophiles NPI and DMAD (notice that carbonyl ylide dimer 13a also results from an intermolecular cycloaddition reaction). With the cysteine-derived diazoesters 8b and c, on the other hand, it appears that the formation of the five-membered cyclic sulfonium ylides 12b and c and of the

Imidazole as a parent π-conjugated backbone in charge-transfer chromophores

• Jiří Kulhánek and
• Filip Bureš

Beilstein J. Org. Chem. 2012, 8, 25–49, doi:10.3762/bjoc.8.4

• (Figure 5, Table 3). Imidazoles 12 (DIYSP, δ = 41 GM, [38][39]) and 13 (FD3, δ = 1556 GM, [40]) were developed as two-photon absorbing and fluorescent A-π-A’ chromophores, which undergo photopolymerization or can be applied as fluorescent sensors for (homo)cysteine. Donor 4,5-disubstituted imidazole

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• -type monooxygenases encoded by the cluster, HctG or HctH, to 2,3-dihydroxyisovaleric acid. Two other NRPS modules contain all the required domains for adenylation and heterocyclization of cysteine, and an FMN-dependent oxidase domain, which is likely involved in thiazole ring formation. The cluster

• multidrug resistance [59]. The patellamide gene cluster consists of seven genes, expression of which in E. coli leads to the production of the peptides [59]. Heterocyclization of serine, cysteine and threonine, respectively is catalyzed by the heterocyclase PatD [60]. In contrast to other heterocyclases

• of bacteria. The characteristic feature of the group is lanthionine bridges, which are formed by dehydration of serine or threonine followed by intramolecular addition of cysteine thiols to the resulting dehydro amino acids. Lantipeptides exhibit a variety of bioactivities, in particular

Ratiometric fluorescent probe for enantioselective detection of D-cysteine in aqueous solution

• Xiao-bo Zhou,
• Wing-Hong Chan,
• Albert W. M. Lee and
• Chi-Chung Yeung

Beilstein J. Org. Chem. 2011, 7, 1508–1515, doi:10.3762/bjoc.7.176

• enantioselective detection of cysteine in 99:1 buffered HEPES:ACN solutions. Under the measuring conditions, the sensor demonstrates high selectivity toward Cys against Hcy and GSH, and an enantioselectivity of 3.35 can be achieved for antipodal forms of Cys. Keywords: chemosensor; D-cysteine; enantioselectivity

• ; fluorescence; ratiometric; Introduction The rapid, sensitive, and selective sensing of biologically relevant thiols including cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) has attracted significant interest in the sensor community (Figure 1) [1]. All three of these thiols are present in living

• ratiometric fluorescent chemosensors for the detection of thiols have been constructed [29][30][31]. Recently, on the basis of a native chemical-ligation reaction, Lin and coworkers reported a FRET-based probe suitable for ratiometric imaging of cysteine in living cells [31]. Therefore, it is a challenging

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• removal of the Boc protecting group and oxidation of the free amino group to the nitro group [13]. This method, however, is not applicable to methionine, tyrosine, tryptophan and cysteine, all of which are sensitive to the oxidation conditions used. As an alternative, Nα-protected amino acids were used to

• -phthalaldehyde/Nα-tert-butyloxycarbonyl-L-cysteine and HPLC analysis, and we concluded that the obtained amide product contained a small amount (1.7%) of the D-isomer resulting from the first step of carboxylate activation rather than the last two steps of selenocarboxylate generation and amidation [20]. In

Photoinduced electron-transfer chemistry of the bielectrophoric N-phthaloyl derivatives of the amino acids tyrosine, histidine and tryptophan

• Axel G. Griesbeck,
• Jörg Neudörfl and
• Alan de Kiff

Beilstein J. Org. Chem. 2011, 7, 518–524, doi:10.3762/bjoc.7.60

• cysteine and S-methyl cysteine derivatives [8]. Other proteinogenic amino acids that, in principle, should also be able to show bielectrophoric behavior with aromatic side chains similar to phenylalanine are tyrosine, histidine and tryptophan. The photochemistry of the phthalimide derivatives of these

pH-Responsive chromogenic-sensing molecule based on bis(indolyl)methene for the highly selective recognition of aspartate and glutamate

• Litao Wang,
• Xiaoming He,
• Yong Guo,
• Jian Xu and
• Shijun Shao

Beilstein J. Org. Chem. 2011, 7, 218–221, doi:10.3762/bjoc.7.29

• observed upon addition of cysteine. On the other hand, no noticeable changes in color and absorption spectra were observed in the presence of various neutral amino acids and basic amino acids under the same conditions (even at much higher amino acids concentrations), which means that the receptor 1

• the protonated receptor [H2L]+. For cysteine, due to its slight acidity compared to neutral and basic amino acids, it may also partly protonate 1, however, the spectral change observed does not achieve the same level as the acidic amino acids even in the presence of 100 equiv of cysteine. On the other

The allylic chalcogen effect in olefin metathesis

• Yuya A. Lin and
• Benjamin G. Davis

Beilstein J. Org. Chem. 2010, 6, 1219–1228, doi:10.3762/bjoc.6.140

• and S-pentenyl cysteine (21b and 21c, respectively), failed to work under identical conditions in aqueous media (Scheme 7a) [17]. In order to compare the relative CM reactivity between other allylic heteroatom derivatives, further studies were carried out on the CM of allyl benzyl ether (23) and allyl

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