Dual functionalized liposomes were developed to cross the blood–brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a < 180 nm diameter with a negative ζ-potential; (ii) were able to cross an in vitro BBB model with an endothelial permeability of 3 ± 1 × 10−5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells.
Grubbs complexes are also useful catalysts to chemoselectively promote intramolecular carbene C–H insertion from amino-tethered α-diazoesters to give pyrrolidines.
The use of Pd-, Rh(II)-and Ru(II)-based catalysts has been explored in the transition metalcatalysed intramolecular carbenoid CÀH insertion of a-diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate-dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)-catalysts were as efficient as [Rh(Ph 3 CCO 2 ) 2 ] 2 in promoting the C(sp 3 )ÀH insertion of ortho-substituted anilines. In contrast, for anilines bearing meta-and para-substituents, the Rh(II)-catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p-cymene)Cl 2 ] 2 was the most efficient catalyst for the insertion reaction of the N-benzyl-N-phenyl and N,N-dibenzyl a-diazoesters, while the C(sp 3 )ÀH insertion of the N-benzylsulfonamide substrate was only promoted by [Rh(Ph 3 CCO 2 ) 2 ] 2 . According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)-and Ru(II)catalysed C(sp 3 )ÀH insertions differs considerably from that typically proposed for the Rh(II)-catalysed transformation. Whereas the Pd(0)-catalysed reaction involves a Pd-mediated 1,5-H migration from the C(sp 3 )ÀH bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)-promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)-catalysed transformation.
In the panorama of sustainable chemistry, the use of green solvents is increasingly emerging for the optimization of more eco-friendly processes which look to a future of biocompatibility and recycling. The green solvent Cyrene, obtained from biomass via a two-step synthesis, is increasingly being introduced as the solvent of choice for the development of green synthetic transformations and for the production of biomaterials, thanks to its interesting biocompatibility, non-toxic and non-mutagenic properties. Our review offers an overview of the most important organic reactions that have been investigated to date in Cyrene as a medium, in particular focusing on those that could potentially lead to the formation of relevant chemical bonds in bioactive molecules. On the other hand, a description of the employment of Cyrene in the production of biomaterials has also been taken into consideration, providing a point-by-point overview of the use of Cyrene to date in the aforementioned fields.
A synthetic method to prepare tetrahydroquinoline‐4‐carboxylic acid esters has been developed through the transition‐metal‐catalyzed intramolecular aromatic C−H functionalization of α‐diazoesters. Both [{Pd(IMes)(NQ)}2] (IMes=1,3‐dimesitylimidazol‐2‐ylidene, NQ=1,4‐naphthoquinone) and the first‐generation Grubbs catalyst proved effective for this purpose. The ruthenium catalyst was found to be the most versatile, although in a few cases the palladium complex afforded better yields or selectivities. According to DFT calculations, Pd0‐ and RuII‐catalyzed sp2‐CAr−H functionalization proceeds through different reaction mechanisms. Thus, the Pd0‐catalyzed reaction involves a Pd‐mediated 1,6‐H migration from the sp2‐CAr−H bond to the carbene carbon atom, followed by a reductive elimination process. In contrast, electrophilic addition of the ruthenacarbene intermediate to the aromatic ring and subsequent 1,2‐proton migration are operative in the Grubbs catalyst promoted reaction.
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