C-Terminally modified peptides are important for the development and delivery of peptide-based pharmaceuticals because they impact peptide activity, stability, hydrophobicity, and membrane ...permeability. Additionally, the vulnerability of C-terminal esters to cleavage by endogenous esterases makes them excellent pro-drugs. Methods for post-SPPS C-terminal functionalization potentially enable access to libraries of modified peptides, facilitating tailoring of their solubility, potency, toxicity, and uptake pathway. Apparently minor structural changes can significantly impact the binding, folding, and pharmacokinetics of the peptide. This review summarizes developments in chemical methods for C-terminal modification of peptides published since the last review on this topic in 2003.
A go-to compilation of recent strategies to access C-terminally modified peptides contextualized by a discussion of the major synthetic challenges that have historically hampered progress in this area.
Biology and Chemistry of the Zoanthamine Alkaloids Behenna, Douglas C; Stockdill, Jennifer L; Stoltz, Brian M
Angewandte Chemie (International ed.),
March 14, 2008, Volume:
47, Issue:
13
Journal Article
Peer reviewed
Marine natural products have long played an important role in natural products chemistry and drug discovery. Mirroring the rich variety and complicated interactions of the marine environment, the ...substances isolated from sea creatures tend to be incredibly diverse in both molecular structure and biological activity. The natural products isolated from the polyps of marine zoanthids are no exception. The zoanthamine alkaloids, the first of which were isolated over 20 years ago, are of particular interest to the synthetic community because they feature a novel structural framework and exhibit a broad range of biological activities. In this Review, we summarize the major contributions to understanding the zoanthamine natural products with regard to their isolation and structure determination, as well as studies on their biological activity and total synthesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A streamlined approach to the tertiary amine-containing core of the calyciphylline A and daphnicyclidin A-type Daphniphyllum alkaloids is presented. A known carvone derivative is converted into the ...core structure in only four synthetic operations, and it is well poised for further elaboration. The key enabling methodology is a radical cyclization cascade beginning with addition of a secondary, neutral aminyl radical to the β-position of an enone, followed by trapping with a pendant alkyne.
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Studies of
-linked glycoconjugates have attracted growing interest because of their enhanced chemical stability and enzymatic resistance over
-glycoside counterparts. We here report a facile approach ...to access α-1,2-
-linked glycosides using triflic acid as a catalyst to promote the glycosylation of a series of thiols with d-glucosamine, galactosamine, glucose, and galactose electrophiles. This method is broadly applicable for the stereoselective synthesis of
-linked glycopeptides, oligosaccharides and glycolipids in high yield and excellent α-selectivity. Many of the synthetic limitations associated with the preparation of these
-linked products are overcome by this catalytic method.
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Recent developments in the use of isonitriles to furnish secondary and tertiary amide bond formations have been applied to a novel total synthesis of the important cyclic polypeptide cyclosporine A. ...Specifically, the disclosed synthetic route demonstrates the utility of microwave-mediated carboxylic acid isonitrile couplings, thioacid isonitrile couplings at ambient temperature, and isonitrile-mediated couplings of carboxylic acids and thioacids with amines to form challenging amide bonds.
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The Daphniphyllum alkaloids remain an attractive target in the synthetic community because of their unique framework and promising biological activities. We have shown that the ABC ...core of the calyciphylline A-type alkaloids can be rapidly accessed via the tandem cyclization of a neutral aminyl radical with a polarized cyclic olefin. Deuterium labeling experiments and reactions omitting a tin hydride reagent suggest that the solvent is the major source of the terminating hydrogen atom in the cyclization cascade. Incorporation of an internal alkyne in the radical pathway was tolerated in the reaction, and it provided the necessary atoms to enable completion of the D ring of the calyciphylline A-type alkaloids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Rapid, selective detection of metals in complex samples remains an elusive goal that could provide critical analytical information for biological and environmental sciences and industrial waste ...management. Fast-scan cyclic voltammetry (FSCV) using carbon-fiber microelectrodes (CFMs) is an emerging technique for metal analysis with broad potential applicability because of its rapid response to changes in analyte concentration and minimal disturbance to the analysis medium. In this communication, we report the first effective application of covalently modified CFMs to achieve highly selective, subsecond Cu(II) measurements using FSCV. A two-part strategy is employed for maximum selectivity: Cu(II) binding is augmented by a covalently grafted ionophore, while binding of other metals is prevented by chemical blocking of nonselective surface adsorption sites. The resulting electrodes selectively detect Cu(II) in a complex medium comprising several interfering metals. Overall, this strategy represents a transformative innovation in real-time electrochemical detection of metal analytes.
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On-resin oxidative cyclization of propargylalanine peptide precursors expedites the production of β-sheet-like peptides to target protein−protein interactions.
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A tin-free strategy for the successful cyclization of a variety of internal alkyne-containing N-chloroamine precursors to the ABC core via cyclization of a neutral aminyl radical is established. ...Deuterium labeling experiments confirm that the solvent is the primary source of the final H atom in the cyclization cascade. These conditions enabled a streamlined route to a β-ketoester intermediate poised for intramolecular Knoevenagel condensation to construct the seven-membered D-ring of calyciphylline A alkaloids. However, exposure to CsF in t-BuOH at elevated temperatures led to an unexpected decarboxylation to form a D-ring-contracted tetracyclic core.
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Studies of S-linked glycoconjugates have attracted growing interest because of their enhanced chemical stability and enzymatic resistance over O-glycoside counterparts. We here report a facile ...approach to access α-1,2-cis-S-linked glycosides using triflic acid as a catalyst to promote the glycosylation of a series of thiols with d-glucosamine, galactosamine, glucose, and galactose electrophiles. This method is broadly applicable for the stereoselective synthesis of S-linked glycopeptides, oligosaccharides and glycolipids in high yield and excellent α-selectivity. Many of the synthetic limitations associated with the preparation of these S-linked products are overcome by this catalytic method.
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IJS, KILJ, NUK, UL, UM, UPUK
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