1. Targeted Treatment of Ischemic Stroke by Bioactive Nanoparticle-Derived Reactive Oxygen Species Responsive and Inflammation-Resolving Nanotherapies
Jichao Yuan, et al. ACS Nano. 2021 Oct 26;15(10):16076-16094. doi: 10.1021/acsnano.1c04753. Epub 2021 Oct 4.
Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticle-derived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxide-eliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen-glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, anti-inflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.
2. Allenylboronic Acid Pinacol Ester: A Selective Partner for [4 + 2] Cycloadditions
Natalia Labadie, Juan M Ramos Marchena, Noelia S Medrán, Silvina C Pellegrinet Org Lett. 2021 Jul 2;23(13):5081-5085. doi: 10.1021/acs.orglett.1c01609. Epub 2021 Jun 21.
We have studied the reaction of allenylboronic acid pinacol ester with cyclopentadiene with experimental and computational methods. The reaction occurred efficiently with complete Diels-Alder periselectivity and regioselectivity at the proximal double bond. The concerted mechanism for the observed transformation was computed to be favored over competitive addition to the distal double bond, [3,3]-sigmatropic rearrangements, and stepwise radical mechanism. This unprecedented Diels-Alder reaction enables the construction of synthetically versatile boron-substituted cycloadducts.
3. Asymmetric transfer hydrogenation of boronic acid pinacol ester (Bpin)-containing acetophenones
Ye Zheng, Martin Wills Org Biomol Chem. 2022 May 11;20(18):3742-3746. doi: 10.1039/d2ob00569g.
A series of Bpin-containing acetophenone derivatives were reduced by asymmetric transfer hydrogenation (ATH), using Noyori-Ikariya catalysts, with formic acid/triethylamine, to alcohols in high ee when the Bpin is in the para- or meta-position. Substrates containing ortho-Bpin groups were reduced in lower ee, with formation of a cyclic boron-containing group. The products were converted to substituted derivatives using Pd-catalysed coupling reactions. The results represent the first examples of ATH of Bpin-containing ketones.
