A novel series of β-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing αβ, αβ, αβ, αβ, αβ, αβ, and αβ integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by αβ, αβ, αβ, or αβ integrin, and antagonists for the integrins αβ and αβ as well as αβ and αβ, preventing the effects elicited by the respective endogenous agonists.

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To replace dimethylformamide (DMF) in fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis, we explored the application of mixtures of green solvents (green solvents mixtures for solid-phase peptide synthesis (GM-SPPS)) as combinations of Cyrene (dihydrolevoglucosenone), sulfolane, or anisole with dimethyl carbonate or diethyl carbonate, in different proportions. Their ability to swell differently functionalized polystyrene and polyethylene glycol resins was explored, and solubility of amino acids and coupling reagents was studied. Moreover, the synthesis of the model peptide Aib-enkephalin was performed in the new green mixtures, confirming the possibility to fully replace DMF all over SPPS. The two established best green protocols were then successfully applied to the synthesis of a longer peptide (Aib-ACP). Finally, the green solvent-based procedure was applied to the synthesis of the reduced form of the active pharmaceutical ingredient (API) Octreotide. After oxidative cyclization and a single high-pressure column chromatography, the pharmaceutical-grade compound was isolated in comparable high yield to that obtained with the standard procedures.

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Developing greener synthetic processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality. In this context, the renaissance of peptides...