Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• introduction of N-terminal modifications. To test the hypothesis of improved internalization behavior of the dimer, we conducted flow-cytometric cellular uptake studies with sC18 versus (sC18)2 in various cell lines after N-terminal labeling with carboxyfluorescein (labeling of the dimer occurred at the N

• /DIC. Synthesis of branched (sC18)2 was achieved by N-terminal coupling of Dde-Lys(Fmoc)-OH to sC18(5-16) and subsequent automated elongation of the peptide chain at the lysine side chain by using Nα-Boc protected glycine at the terminal position. Cleavage of the Dde group was achieved by treatment

• with a 3% solution of hydrazine in DMF for 12 × 10 min. Subsequently, the peptide was elongated to its final length by automated SPPS. N-terminal coupling of Cym2 or 5(6)-carboxyfluorescein was carried out by using 2 equiv of the substance to be coupled and activation with 2 equiv of HATU/DIPEA in DMF

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

• of small synthetic arginine and tryptophan containing peptides was prepared and analyzed for their antibacterial activity. The effect of N-terminal substitution with metallocenoyl groups such as ferrocene (FcCO) and ruthenocene (RcCO) was investigated. Antibacterial activity in different media

• , growth inhibition, and killing kinetics of the most active peptides were determined. The toxicity of selected derivatives was determined against erythrocytes and three human cancer cell lines. It was shown that the replacement of an N-terminal arginine residue with a metallocenoyl moiety modulates the

• of the N-terminal arginine residue in non-toxic and non-hemolytic (RW)3 peptides can modulate the kinetics of the peptide’s antibacterial activity. Acetylation completely suppresses this activity. In comparison, replacement of the N-terminal arginine residue with the organometallic ferrocenoyl moiety

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

• N-terminal amino group at the activated carbonyl group provided cleavage of the cyclized β-tripeptide from the resin. Purification did not require any chromatography since organization by intermolecular hydrogen bonding resulted in decreased solubility and precipitation of the β-tripeptide template

• (N3)-β3-HLys(Cbz)) (4). The peptide sequence H-β3-HLys(Fmoc)-β3-HLys(N3)-β3-HLys(Cbz)-OH was synthesized on 4-Fmoc-hydrazinobenzoyl AM NovaGel resin (0.700 mmol/g, 1.00 g, 7.00 mmol, 1.00 equiv). After N-terminal Fmoc deprotection (20% piperidine in DMF, 3.50 mL, 20 min), standard Boc protocols were

• used for coupling (β-amino acid 5.00 equiv, HBTU 4.50 equiv, HOBt 5.00 equiv, DIEA 10.0 equiv, 2.80 mL DMF, 18 h) and Boc cleavage (3.00 mL TFA/m-cresole–95/5 v/v, 2 × 2 min) of β-amino acids Boc-β3-HLys(Fmoc)-OH, Boc-β3-HLys(Cbz)-OH and Boc-β3-HLys(N3)-OH. After N-terminal deprotection of the last

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

• the synthesis of 2 by a macrolactonization approach is 4 (Scheme 1), in which the N-terminal amino group of the L-Thr residue is protected while the side-chain hydroxy group is free. The Cbz group was chosen as a suitable protecting group for the N-terminus. The D-Asn and D-allo-Thr residues were the

Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

• Evan F. Haney,
• Leonard T. Nguyen,
• David J. Schibli and
• Hans J. Vogel

Beilstein J. Org. Chem. 2012, 8, 1172–1184, doi:10.3762/bjoc.8.130

• peptide with a backbone root-mean-square deviation (RMSD) of 0.630 Å (Figure 7). It appears that the structure is slightly bent, especially in the N-terminal region, which lies well below the plane of the helix formed by residues 7–19. The side-chain distribution of gp41w-4R in the cosolvent solution

• backbone RMSD of 0.389 Å (Figure 7). In agreement with the structure of gp41w-4R, the N-terminal region of gp41w-KA is not aligned with the C-terminal helix formed across residues 7–19 and these first six residues appear to form a slightly extended conformation. This may be an important structural feature

• this model, the N-terminal region of gp41w-KA would then be oriented into the bilayer, which would bring the Lys residues at positions 1, 4 and 5 into the hydrophobic core of the bilayer. This may be related to the membrane-destabilizing properties of the gp41w-KA peptide. The gp41w-FKA peptide has a

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

• -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

• chromatography are summarized in Table 1. In ligation reactions employing the N-terminal Cys-peptide 3, nearly complete conversion was determined after five hours, but stirring was nevertheless continued overnight (Table 1, entries 1 and 4). For peptide 5 containing the 4,5,6-trimethoxy-2-mercaptobenzyl

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

• synthetic glycoproteins. Since the discovery of native chemical ligation (NCL) by Kent and co-workers, numerous efforts have been made to prepare challenging protein targets [39][40][41][42][43][44]. In the NCL method, a native amide bond is formed by coupling of a C-terminal thioester with the N-terminal

• 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

• fragment, (β-FSH 28–111) was obtained by ligation of two shorter synthetically prepared peptides followed by sequential coupling of two N-terminal glycopeptide fragments (β-FSH 1–19 and 20–27) employing standard NCL conditions. Binding of the hFSH glycoprotein to its receptor stimulates the maturation of

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

• through imino bond formation between the N-terminal and C-terminal amino acids. The responsible enzyme NcpB contains a C-terminal reductase domain that has been shown to catalyze the reductive release of the peptide from the synthetase as an aldehyde followed by spontaneous formation of the imino head-to

• /MvdD) and one ω-amide linkage between lysine and aspartate (MdnB/MvdC) (Figure 10) [64][65]. Microviridins can be heterologously produced in E. coli [65]. Cyclizations occur in a strictly defined order. Ring size and composition of the microviridin core peptide is invariant [66], whereas N-terminal and

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• processes. Furthermore, the catalyst lifetime can, in many cases, be dramatically improved under supercritical conditions, owing to reduced coking [69][70]. The selective monoprotection of 1,n-terminal diols is a characteristic example of how mono-substituted ethers can be selectively prepared versus the

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• followed by spontaneously nucleophilic attack on the cyano group by the N-terminal nitrogen of the hydrazine substitutent (Scheme 42). Beam et al. [85] have reported a novel synthesis of 5-aminopyrazoles 155 from polylithiated C(α), N-thiosemicarbazones (X = S) or C(α), N-semicarbazones (X = O). The

Expanding the gelation properties of valine-based 3,5-diaminobenzoate organogelators with N-alkylurea functionalities

• Hak-Fun Chow and
• Chin-Ho Cheng

Beilstein J. Org. Chem. 2010, 6, 1015–1021, doi:10.3762/bjoc.6.114

• that further intermolecular hydrogen bonding occurred during gel formation. Conclusion We have reported the synthesis of novel valine-containing 3,5-diaminobenzoate derivatives 2 with additional N-alkylurea functionality at the N-terminal of the valine residues. The resulting organogelators were found

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• dipeptidyl peptidase-4 (DPP-4; CD26; E.C. 3.4.14.5) by small molecules has emerged as one of the key approaches for the treatment of type-2 diabetes [1][2][3][4][5]. DPP-4, a member of the prolyl oligopeptidase family of serine protease, cleaves the N-terminal dipeptide from peptides with proline or alanine

Synthesis of glycosylated β³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

• Florian Karch and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2010, 6, No. 47, doi:10.3762/bjoc.6.47

• of the epithelial mucin MUC1 and an N-terminal non-immunogenic triethylene glycol spacer. The latter can be used for further conjugation to immunostimulants (e.g., BSA [35] or tetanus toxoid [36]) and for immobilisation onto microarray platforms [37] within functional immunological studies. The MUC1

• Fmoc-Val-OH were employed. In every coupling cycle, the N-terminal Fmoc group was removed by treatment of the resin with a solution of piperidine (20%) in NMP for at least 3 × 2.5 min. The coupling of the amino acids (1 mmol or 10 equiv based on the loaded resin) was carried out with HBTU (1 mmol

• coupled using HBTU (1 mmol), HOBt (1 mmol) and DIPEA (2 mmol) in DMF (20–30 min vortex) and the N-terminal Fmoc group was removed by piperidine (20%) in NMP. Detachment from the resin and simultaneous removal of all side chain protecting groups was performed in a Merrifield glass reactor by shaking with

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

Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine- 2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors

• Santosh K. Singh,
• Narendra Manne and
• Manojit Pal

Beilstein J. Org. Chem. 2008, 4, No. 20, doi:10.3762/bjoc.4.20

• molecules [1][2][3]. DPP-IV, a member of the prolyl oligopeptidase family of serine protease, cleaves the N-terminal dipeptide from peptides with proline or alanine in the second position. As a result of intense pharmaceutical research, several DPP-IV inhibitors have been discovered and a few of them