synthesis-stimuli-responsive-nanogels-using-aqueous-one-step

Synthesis of Stimuli-responsive Nanogels using Aqueous One-step Crosslinking and Co-nanopolymerization

Nanogels consisting of crosslinked-polymeric nanoparticles have been developed for the delivery of numerous chemical and biological therapeutics, owing to ...

Imperial College London

Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides-extremely common pharmacophores-but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.

Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides.

A novel PLGA-inspired NP polymerization technique is presented, which allows the formation of NPs via the cross-linking of precisely sequenced short oligolactoglycolic acid dimethacrylates (OLGADMAs). Following the synthesis of a range of OLGADMAs, a library of NPs via this rapid and surfactant-free nanopolymerization method is successfully generated, which permits the simultaneous NP formation and encapsulation of drugs such as dexamethasone. The results indicate that NPs produced through this nanopolymerization technique with precisely controlled sequences exhibit heightened stability compared to conventionally sequenced and non-sequence controlled PLGA, as evidenced by minimal pH changes over five weeks. This improved stability is attributed to simultaneous crosslinking and co-polymerization of the OLGADMAs. Moreover, the long-acting NPs demonstrate minimal cytotoxicity and uniform cellular uptake in vitro. It is concluded that the ability to precisely regulate the sequence of short PLGA-inspired monomers and employ a unique in situ nanopolymerizing reaction results in exceptionally stable NPs for sustained drug delivery and opens exciting possibilities for the development of a range of long-lasting drug delivery systems with programmable structure and function.

Long-Lasting Cross-Linked PLGA-Inspired Nanoparticles from One-Pot Nanopolymerization of Precisely Sequenced Short Oligolactoglycolic Acid Dimethacrylates.

Article	Year
Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides. Nature chemistry\| PubMed ID: 35087220	2022
Long-Lasting Cross-Linked PLGA-Inspired Nanoparticles from One-Pot Nanopolymerization of Precisely Sequenced Short Oligolactoglycolic Acid Dimethacrylates. Macromolecular rapid communications\| PubMed ID: 39838613	2025

Luka Blagojevic

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