Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an α-helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis.
Nitrosocarbonyl
mesitylene intermediate undergoes an ene reaction
with cinnamyl alcohol affording the corresponding 5-hydroxy-isoxazolidine
in fair yields. The synthesized 5-acetoxy-isoxazolidine serves as
synthon for the preparation of 6-chloropurine N,O-nucleoside analogues,
according to the Vorbrüggen reaction. The compounds were evaluated
for their metabolic and apoptotic activity, and their structure–activity
relationship is discussed.
Anthracenenitrile
oxide undergoes 1,3-dipolar cycloaddition reactions
with 1-substituted-4-(prop-2-yn-1-yloxy)benzene affording the expected
isoxazoles in good yields and as single regioisomers. N–O Bond
cleavage and boron complexation afforded the corresponding boron complexes,
derivatized with either a triple bond for click-chemistry applications
or an oxime group for nitrile oxide 1,3-dipolar cycloaddition. The
optical properties of these compounds show potential for employment
as fluorescent tags in imaging techniques. The activity-based protein
profiling assays showed good reactivity for the synthesized probes
even with short peptide chains (epoxomicin). Scope and limitations
are discussed in the light of the obtained results.
A modified pathway towards 5-hydroxy-isoxazolidines has been preliminarily investigated by taking advantage of the anti-Markovnikov route in ene reactions of sterically encumbered nitrosocarbonyl intermediates in the presence of allylsilylethers. Fluoride-mediated deprotection/cyclization of the ene adducts afforded the desired heterocycles in quantitative yields and the methodology is adaptable to a one-pot procedure.[a] Dr. Scheme 3. Synthesis of protected allylic alcohols as silylethers. Scheme 4. Ene reactions of mesito nitrosocarbonyl 8 M with allylsilylethers 16 a-c(A). Yields (%) of the isolated compounds 10, 17 and 18. Mes = 2,4,6-Me 3 Ph.
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