RESUMO
The development of straightforward and versatile peptide cyclisation methods is highly desired to meet the demand for more stable peptide-based drugs. Herein, a new method for the synthesis of side-chain-to-tail cyclic peptides with the simultaneous introduction of an N-terminal handle, based on the introduction of an N-terminal thiolactone building block, is described. A primary amine liberates a homocysteine analogue from the thiolactone building block, which further enables cyclisation of the peptide through disulfide-bond formation with a C-terminal cysteamine. Postcyclisation modification can be achieved by using small bifunctional amines. Alternatively, the synthesis of lipopeptides is demonstrated through direct thiolactone opening with long-chain alkyl amines.
Assuntos
Lactonas/química , Peptídeos Cíclicos/síntese química , Compostos de Sulfidrila/química , Estrutura Molecular , Peptídeos Cíclicos/químicaRESUMO
We here describe a furan oxidation based site-specific chemical ligation approach using unprotected peptide segments. This approach involves two steps: after photooxidation of a furan-containing peptide, ligation is achieved by reaction of the unmasked keto-enal with C- or N-terminal α-nucleophilic moieties of the second peptide such as hydrazine or hydrazide to form a pyridazinium or pyrrolidinone linkage respectively.
Assuntos
Peptídeos/química , Oxigênio Singlete , Sequência de Aminoácidos , Ligação ProteicaRESUMO
A novel chemoselective ligation methodology has been developed for the facile construction of peptide-based fluorescent probes. Furan-containing peptides were activated by singlet oxygen and covalently engaged by nitrogen nucleophiles to yield stable conjugates. Singlet oxygen was compatible with sensitive amino acid residues within the peptides and a range of fluorophores, bearing different functionalities, were successfully incorporated, illustrating the broad scope of the developed strategy.
Assuntos
Furanos/química , Peptídeos/química , Oxigênio Singlete/química , Catálise , Corantes Fluorescentes/química , Luz , OxirreduçãoRESUMO
All-in-one: A new and general one-pot reaction sequence initiated by singlet oxygen that transforms simple furan substrates into complex nitrogen-bearing aromatic polycycles having all the structural features of a number of important natural products (for example, the erythrina alkaloids; see scheme, RB = rose Bengal) is reported. The reaction sequence itself uses mild conditions and has wide functional group tolerance.
RESUMO
Recent dramatic expansion in potential uses of protein conjugates has fueled the development of a wide range of protein modification methods; however, the desirable single-site multi-functionalization of proteins has remained a particularly intransigent challenge. Herein, we present the application of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones (5HP2Os) as advantageous alternatives to widely used maleimides for the chemo- and site-selective labeling of cysteine residues within proteins. A variety of 5HP2O building blocks have been synthesized using a one-pot photooxidation reaction starting from simple and readily accessible furans and using visible light and oxygen. These novel reagents display excellent cysteine selectivity and also yield thiol conjugates with superior stability. 5HP2O building blocks offer a unique opportunity to introduce multiple new functionalities into a protein at a single site and in a single step, thus, significantly enhancing the resultant conjugate's properties.
RESUMO
A range of 1-azaspirocycles, spiroaminals and 1,6-diazaspirocycles has been synthesized, starting from simple and readily accessible furan precursors, using a cascade reaction sequence initiated by singlet oxygen.
Assuntos
Compostos Aza/química , Furanos/química , Compostos de Espiro/química , Ciclização , Luz , Oxirredução , Oxigênio Singlete/química , Compostos de Espiro/síntese químicaRESUMO
Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2-pyrrolidinone formation, cyclization of the pendant aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used to achieve a rapid and highly effective formal synthesis of erysotramidine.