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Acrylic boronate: a multifunctional C3 building block for catalytic synthesis of rare organoborons and chemoselective heterobifunctional ligations.

ABSTRACT: A novel C3 acylboron building block; acrylic boronate was successfully prepared and its versatility for catalytic synthesis of several previously inaccessible organoborons is described. Cross-metathesis and Pd-catalyzed coupling of acrylic boronate enabled two complementary routes to highly functionalized α,β-unsaturated acylborons and two new types of conjugated borylated products: α,β,γ,δ-unsaturated and bis-α,β unsaturated acylborons. The synthetic application of α,β-unsaturated acylborons was demonstrated for the first time, thereby providing a general and highly regioselective route to medicinally important 3-boryl pyrazoles. Acrylic boronate also provided a unique bis-electrophilic platform for rapid and chemoselective labeling of cysteines with acylboron tags which are potentially useful for site-selective functionalization and orthogonal ligation of proteins.

SUBMITTER: Lin S

PROVIDER: S-EPMC8188605 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dendrimers have emerged as multifunctional carriers for targeted drug delivery, gene delivery and imaging. Improving the functional versatility at the surface for carrying multiple conjugation reactions is becoming vital. Typically, generation four polyamidoamine (G4-PAMAM) dendrimers bear approximately 64 symmetrical end groups, often requiring different spacers to conjugate various functional groups (drugs and targeting moities), increasing the synthetic steps. In the present study, a simple one-step synthesis to convert each symmetrical end group of G4-PAMAM dendrimers into two reactive, distinct orthogonal and chemoselective groups is described. A near-complete end-capping of the dendrimers (87-93%) with amino acids results in heterobifunctional G4-PAMAM dendrimers bearing a very high (> or = 110) diverse peripheral end groups (OH+NHBoc, OH+COOMe, SH+NHBoc, and COOH+NHBoc). Postfunctionalization ability of these dendrimers was evaluated. The heterobifunctional groups at the dendrimer periphery could be chemoselectively conjugated to multiple moities such as drugs (indomethacin and dexamethasone) and drugs and imaging agents (dexamethasone and FITC). These conjugations could be achieved in immediate succession without functional group conversions, eliminating the additional elaborate synthetic steps traditionally required to append specific linkers. Furthermore, one of the two functional handles at periphery was used to develop in situ forming hydrogels, whereas the other handle could be used for conjugating the drugs (e.g., dexamethasone). The heterobifunctional dendrimers with either "NH(2) or SH (thiopyridyl protected form)" terminations showed in situ hydrogel formation by cross-linking with N-hydroxysuccinimide or thiol-terminated multiarm polyethylene glycol (20 kDa). The choice of amino acids as versatile linkers would enable biocompatible dendrimer scaffolds for use in drug delivery. Zeta-potential measurements showed drastic lowering of the charge on G4-PAMAM-NH(2) dendrimers by end-capping with amino acids, whereas in the case of neutral G4-PAMAM-OH dendrimers, the charge did not increase or decrease substantially. The in vitro cytotoxicity and hemolysis assay showed that the heterobifunctional dendrimers were noncytotoxic in the 100 ng/mL to 1 mg/mL concentration range. With this study, we demonstrate the development of biocompatible dendrimers bearing multiple orthogonal surface groups, enabling the attachment of drugs, imaging agents, and gel formation using minimal synthetic steps.

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Acrylic boronate: a multifunctional C3 building block for catalytic synthesis of rare organoborons and chemoselective heterobifunctional ligations.

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