R&D｜Nature Communications
引言
1
Fully automated fast-flow synthesis of antisense phosphorodiamidate morpholino oligomers
Chengxi Li,
Alex J. Callahan,
Mark D. Simon,
Kyle A. Totaro,
Alexander J. Mijalis,
Kruttika-Suhas Phadke,
Genwei Zhang,
Nina Hartrampf,
Carly K. Schissel,
Ming Zhou,
Hong Zong,
Gunnar J. Hanson,
Andrei Loas,
Nicola L. B. Pohl,
David E. Verhoeven &
Bradley L. Pentelute
Nature Communications volume 12, Article number: 4396 (2021) Cite this article
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Abstract
Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases.
2
Copper(I)-catalysed site-selective C(sp3)–H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T
Jianwen Jin,
Yichao Zhao,
Sara Helen Kyne,
Kaveh Farshadfar,
Alireza Ariafard &
Philip Wai Hong Chan
Nature Communications volume 12, Article number: 4065 (2021) Cite this article
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Abstract
Strategies that enable intermolecular site-selective C–H bond functionalisation of organic molecules provide one of the cornerstones of modern chemical synthesis. In chloroalkane synthesis, such methods for intermolecular site-selective aliphatic C–H bond chlorination have, however, remained conspicuously rare. Here, we present a copper(I)-catalysed synthetic method for the efficient site-selective C(sp3)–H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T at room temperature. A key feature of the broad substrate scope is tolerance to unsaturation, which would normally pose an immense challenge in chemoselective aliphatic C–H bond functionalisation. By unlocking dichloramine-T’s potential as a chlorine radical atom source, the product site-selectivities achieved are among the most selective in alkane functionalisation and should find widespread utility in chemical synthesis. This is exemplified by the late-stage site-selective modification of a number of natural products and bioactive compounds, and gram-scale preparation and formal synthesis of two drug molecules
3
Direct and selective access to amino-poly(phenylene vinylenes)s with switchable properties by dimerizing polymerization of aminoaryl carbenes
Quentin Sobczak,
Aravindu Kunche,
Damien Magis,
Daiann Sosa Carrizo,
Karinne Miqueu,
Jean-Marc Sotiropoulos,
Eric Cloutet,
Cyril Brochon,
Yannick Landais,
Daniel Taton &
Joan Vignolle
Nature Communications volume 12, Article number: 4093 (2021) Cite this article
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Despite the ubiquity of singlet carbenes in chemistry, their utility as true monomeric building blocks for the synthesis of functional organic polymers has been underexplored. In this work, we exploit the capability of purposely designed mono- and bis-acyclic amino(aryl)carbenes to selectively dimerize as a general strategy to access diaminoalkenes and hitherto unknown amino-containing poly(p-phenylene vinylene)s (N-PPV’s). The unique selectivity of the dimerization of singlet amino(aryl)carbenes, relative to putative C-H insertion pathways, is rationalized by DFT calculations. Of particular interest, unlike classical PPV’s, the presence of amino groups in α-position of C=C double bonds in N-PPV’s allows their physico-chemical properties to be manipulated in different ways by a simple protonation reaction. Hence, depending on the nature of the amino group (iPr2N vs. piperidine), either a complete loss of conjugation or a blue-shift of the maximum of absorption is observed, as a result of the protonation at different sites (nitrogen vs. carbon). Overall, this study highlights that singlet bis-amino(aryl)carbenes hold great promise to access functional polymeric materials with switchable properties, through a proper selection of their substitution pattern.
4
A curved host and second guest cooperatively inhibit the dynamic motion of corannulene
Yang Yang,
Tanya K. Ronson,
Zifei Lu,
Jieyu Zheng,
Nicolas Vanthuyne,
Alexandre Martinez &
Jonathan R. Nitschke
Nature Communications volume 12, Article number: 4079 (2021) Cite this article
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Abstract
Biomolecular systems show how host–guest binding can induce changes in molecular behavior, which in turn impact the functions of the system. Here we report an artificial host–guest system where dynamic adaptation during guest binding alters both host conformation and guest dynamics. The self-assembled cage host employed here possesses concave walls and a chirotopic cavity. Complementarity between the curved surfaces of fullerenes and the inner surface of the host cavity leads the host to reconfigure stereochemically in order to bind these guests optimally. The curved molecule corannulene undergoes rapid bowl-to-bowl inversion at room temperature. Its inversion barrier is increased upon binding, however, and increased further upon formation of a ternary complex, where corannulene and a cycloalkane are both bound together. The chiral nature of the host also leads to clear differences in the NMR spectra of ternary complexes involving corannulene and one or the other enantiomer of a chiral guest, which enables the determination of enantiomeric excess by NMR.
5
4D polycarbonates via stereolithography as scaffolds for soft tissue repair
Andrew C. Weems,
Maria C. Arno,
Wei Yu,
Robert T. R. Huckstepp &
Andrew P. Dove
Nature Communications volume 12, Article number: 3771 (2021) Cite this article
1982 Accesses
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Abstract
3D printing has emerged as one of the most promising tools to overcome the processing and morphological limitations of traditional tissue engineering scaffold design. However, there is a need for improved minimally invasive, void-filling materials to provide mechanical support, biocompatibility, and surface erosion characteristics to ensure consistent tissue support during the healing process. Herein, soft, elastomeric aliphatic polycarbonate-based materials were designed to undergo photopolymerization into supportive soft tissue engineering scaffolds. The 4D nature of the printed scaffolds is manifested in their shape memory properties, which allows them to fill model soft tissue voids without deforming the surrounding material. In vivo, adipocyte lobules were found to infiltrate the surface-eroding scaffold within 2 months, and neovascularization was observed over the same time. Notably, reduced collagen capsule thickness indicates that these scaffolds are highly promising for adipose tissue engineering and repair.
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Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins
Zhiwen Liu,
Fanglong Zhao,
Boyang Zhao,
Jie Yang,
Joseph Ferrara,
Banumathi Sankaran,
B. V. Venkataram Prasad,
Biki Bapi Kundu,
George N. Phillips Jr.,
Yang Gao,
Liya Hu,
Tong Zhu &
Xue Gao
Nature Communications volume 12, Article number: 4158 (2021) Cite this article
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Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible β-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.
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Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
Anna V. Elleman,
Gabrielle Devienne,
Christopher D. Makinson,
Allison L. Haynes,
John R. Huguenard &
J. Du Bois
Nature Communications volume 12, Article number: 4171 (2021) Cite this article
1437 Accesses
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Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaVs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaVs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial NaV block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.
8
Practical iridium-catalyzed direct α-arylation of N-heteroarenes with (hetero)arylboronic acids by H2O-mediated H2 evolution
Liang Cao,
He Zhao,
Rongqing Guan,
Huanfeng Jiang,
Pierre. H. Dixneuf &
Min Zhang
Nature Communications volume 12, Article number: 4206 (2021) Cite this article
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Despite the widespread applications of 2-(hetero)aryl N-heteroarenes in numerous fields of science and technology, universal access to such compounds is hampered due to the lack of a general method for their synthesis. Herein, by a H2O-mediated H2-evolution cross-coupling strategy, we report an iridium(III)-catalyzed facile method to direct α-arylation of N-heteroarenes with both aryl and heteroaryl boronic acids, proceeding with broad substrate scope and excellent functional compatibility, oxidant and reductant-free conditions, operational simplicity, easy scalability, and no need for prefunctionalization of N-heteroarenes. This method is applicable for structural modification of biomedical molecules, and offers a practical route for direct access to 2-(hetero)aryl N-heteroarenes, a class of potential cyclometalated C^N ligands and N^N bidentate ligands that are difficult to prepare with the existing α-C-H arylation methods, thus filling an important gap in the capabilities of synthetic organic chemistry
9
Nanoscale cooperative adsorption for materials control
Rong Ye,
Ming Zhao,
Xianwen Mao,
Zhaohong Wang,
Diego A. Garzón,
Heting Pu,
Zhiheng Zhao &
Peng Chen
Nature Communications volume 12, Article number: 4287 (2021) Cite this article
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Adsorption plays vital roles in many processes including catalysis, sensing, and nanomaterials design. However, quantifying molecular adsorption, especially at the nanoscale, is challenging, hindering the exploration of its utilization on nanomaterials that possess heterogeneity across different length scales. Here we map the adsorption of nonfluorescent small molecule/ion and polymer ligands on gold nanoparticles of various morphologies in situ under ambient solution conditions, in which these ligands are critical for the particles’ physiochemical properties. We differentiate at nanometer resolution their adsorption affinities among different sites on the same nanoparticle and uncover positive/negative adsorption cooperativity, both essential for understanding adsorbate-surface interactions. Considering the surface density of adsorbed ligands, we further discover crossover behaviors of ligand adsorption between different particle facets, leading to a strategy and its implementation in facet-controlled synthesis of colloidal metal nanoparticles by merely tuning the concentration of a single ligand.
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Rapid electron transfer via dynamic coordinative interaction boosts quantum efficiency for photocatalytic CO2 reduction
Jia-Wei Wang,
Long Jiang,
Hai-Hua Huang,
Zhiji Han &
Gangfeng Ouyang
Nature Communications volume 12, Article number: 4276 (2021) Cite this article
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The fulfillment of a high quantum efficiency for photocatalytic CO2 reduction presents a key challenge, which can be overcome by developing strategies for dynamic attachment between photosensitizer and catalyst. In this context, we exploit the use of coordinate bond to connect a pyridine-appended iridium photosensitizer and molecular catalysts for CO2 reduction, which is systematically demonstrated by 1H nuclear magnetic resonance titration, theoretical calculations, and spectroscopic measurements. The mechanistic investigations reveal that the coordinative interaction between the photosensitizer and an unmodified cobalt phthalocyanine significantly accelerates the electron transfer and thus realizes a remarkable quantum efficiency of 10.2% ± 0.5% at 450 nm for photocatalytic CO2-to-CO conversion with a turn-over number of 391 ± 7 and nearly complete selectivity, over 4 times higher than a comparative system with no additional interaction (2.4%±0.2%). Moreover, the decoration of electron-donating amino groups on cobalt phthalocyanine can optimize the quantum efficiency up to 27.9% ± 0.8% at 425 nm, which is more attributable to the enhanced coordinative interaction rather than the intrinsic activity. The control experiments demonstrate that the dynamic feature of coordinative interaction is important to prevent the coordination occupancy of labile sites, also enabling the wide applicability on diverse non-noble-metal catalysts.
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Copper catalyzed late-stage C(sp3)-H functionalization of nitrogen heterocycles
Zhe Chang,
Jialin Huang,
Si Wang,
Geshuyi Chen,
Heng Zhao,
Rui Wang &
Depeng Zhao
Nature Communications volume 12, Article number: 4342 (2021) Cite this article
1400 Accesses
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Nitrogen heterocycle represents a ubiquitous skeleton in natural products and drugs. Late-stage C(sp3)-H bond functionalization of N-heterocycles with broad substrate scope remains a challenge and of particular significance to modern chemical synthesis and pharmaceutical chemistry. Here, we demonstrate copper-catalysed late-stage C(sp3)-H functionalizaion of N-heterocycles using commercially available catalysts under mild reaction conditions. We have investigated 8 types of N-heterocycles which are usually found as medicinally important skeletons. The scope and utility of this approach are demonstrated by late-stage C(sp3)-H modification of these heterocycles including a number of pharmaceuticals with a broad range of nucleophiles, e.g. methylation, arylation, azidination, mono-deuteration and glycoconjugation etc. Preliminary mechanistic studies reveal that the reaction undergoes a C-H fluorination process which is followed by a nucleophilic substitution.
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Organozinc pivalates for cobalt-catalyzed difluoroalkylarylation of alkenes
Xinyi Cheng,
Xingchen Liu,
Shengchun Wang,
Ying Hu,
Binjing Hu,
Aiwen Lei &
Jie Li
Nature Communications volume 12, Article number: 4366 (2021) Cite this article
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Installation of fluorine into pharmaceutically relevant molecules plays a vital role in their properties of biology or medicinal chemistry. Direct difunctionalization of alkenes and 1,3-dienes to achieve fluorinated compounds through transition-metal catalysis is challenging, due to the facile β-H elimination from the Csp3‒[M] intermediate. Here we report a cobalt-catalyzed regioselective difluoroalkylarylation of both activated and unactivated alkenes with solid arylzinc pivalates and difluoroalkyl bromides through a cascade Csp3‒Csp3/Csp3‒Csp2 bond formation under mild reaction conditions. Indeed, a wide range of functional groups on difluoroalkyl bromides, olefins, 1,3-dienes as well as (hetero)arylzinc pivalates are well tolerated by the cobalt-catalyst, thus furnishing three-component coupling products in good yields and with high regio- and diastereoselectivity. Kinetic experiments comparing arylzinc pivalates and conventional arylzinc halides highlight the unique reactivity of these organozinc pivalates. Mechanistic studies strongly support that the reaction involves direct halogen atom abstraction via single electron transfer to difluoroalkyl bromides from the in situ formed cobalt(I) species, thus realizing a Co(I)/Co(II)/Co(III) catalytic cycle.