Reactions of 1,2,4-Oxadiazole[4,5-a]piridinium Salts with Alcohols: the Synthesis of Alkoxybutadienyl 1,2,4-Oxadiazoles.

1,2,4-Oxadiazole[4,5-a]piridinium salts add alcohols and alkoxides to undergo electrocyclic ring opening affording alkoxybutadienyl 1,2,4-oxadiazole derivatives. The pyridinium salts represent a special class of Zincke salts that are prone to rearrange to give alkoxybutadienyl 1,2,4-oxadiazoles when treated with suitable nucleophiles or, alternatively, to give pyridones in the presence of bicarbonate. The pivotal tuning of the experimental conditions leads to a straightforward synthesis of valuable 1,2,4-oxadiazole derivatives. The mechanism is also discussed in the light of previous observations.

Stapled Peptides-A Useful Improvement for Peptide-Based Drugs.

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.

Scope and Limitations of Boron Fluorescent Complexes from Stable Nitrile Oxides in ABPP Assays.

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.

Fluorescent Probes from Aromatic Polycyclic Nitrile Oxides: Isoxazoles versus Dihydro-1λ3,3,2λ4-Oxazaborinines.

Anthracenenitrile oxide undergoes 1,3-dipolar cycloaddition reaction with propargyl bromide affording the expected isoxazole as single regioisomer, suitably synthetically elaborated and functionalized with a protected triple bond. The introduction of a bromine atom at the position C10 of the anthracene moiety allows for inserting a variety of aromatic and heterocyclic substituents through Suzuki coupling. A two-way synthetic route can lead to simple isoxazole derivatives or, after N-O bond reductive cleavage and BF3 complexation, enamino ketone boron complexes. The photophysical properties of both the substituted isoxazoles and the corresponding boron complexes were investigated to show the potentialities for the employment as fluorescent tags in imaging techniques. The quite good quantum yield values confirm the suitability of these compounds in the cellular environment. Scope and limitations of the methodology are discussed.

Ene Reaction of Nitrosocarbonyl Mesitylene with the Cinnamyl Alcohol: Metabolic Activity and Apoptosis of the Synthetized 6-Chloropurine N,O-Nucleoside Analogues.

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.