GSTDTAP

浏览/检索结果: 共6条,第1-6条 帮助

已选(0)清除 条数/页:   排序方式:
Preparation of cyclohexene isotopologues and stereoisotopomers from benzene 期刊论文
NATURE, 2020, 581 (7808) : 288-+
作者:  Shimazaki, Yuya;  Schwartz, Ido;  Watanabe, Kenji;  Taniguchi, Takashi;  Kroner, Martin;  Imamoglu, Atac
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine(1). Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules(1). Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington'  s disease(2), was recently approved by the United States'  Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial(1,3,4). The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound(5), improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug(6,7), these processes are often unselective and the stereoisotopic purity can be difficult to measure(7,8). Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.


Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.


  
Loopy Levy flights enhance tracer diffusion in active suspensions 期刊论文
NATURE, 2020, 579 (7799) : 364-+
作者:  Hu, Bo;  Jin, Chengcheng;  Zeng, Xing;  Resch, Jon M.;  Jedrychowski, Mark P.;  Yang, Zongfang;  Desai, Bhavna N.;  Banks, Alexander S.;  Lowell, Bradford B.;  Mathis, Diane;  Spiegelman, Bruce M.
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

A theoretical framework describing the hydrodynamic interactions between a passive particle and an active medium in out-of-equilibrium systems predicts long-range Levy flights for the diffusing particle driven by the density of the active component.


Brownian motion is widely used as a model of diffusion in equilibrium media throughout the physical, chemical and biological sciences. However, many real-world systems are intrinsically out of equilibrium owing to energy-dissipating active processes underlying their mechanical and dynamical features(1). The diffusion process followed by a passive tracer in prototypical active media, such as suspensions of active colloids or swimming microorganisms(2), differs considerably from Brownian motion, as revealed by a greatly enhanced diffusion coefficient(3-10) and non-Gaussian statistics of the tracer displacements(6,9,10). Although these characteristic features have been extensively observed experimentally, there is so far no comprehensive theory explaining how they emerge from the microscopic dynamics of the system. Here we develop a theoretical framework to model the hydrodynamic interactions between the tracer and the active swimmers, which shows that the tracer follows a non-Markovian coloured Poisson process that accounts for all empirical observations. The theory predicts a long-lived Levy flight regime(11) of the loopy tracer motion with a non-monotonic crossover between two different power-law exponents. The duration of this regime can be tuned by the swimmer density, suggesting that the optimal foraging strategy of swimming microorganisms might depend crucially on their density in order to exploit the Levy flights of nutrients(12). Our framework can be applied to address important theoretical questions, such as the thermodynamics of active systems(13), and practical ones, such as the interaction of swimming microorganisms with nutrients and other small particles(14) (for example, degraded plastic) and the design of artificial nanoscale machines(15).


  
Automated radial synthesis of organic molecules 期刊论文
NATURE, 2020, 579 (7799) : 379-+
作者:  van den Brink, Susanne C.;  Alemany, Anna;  van Batenburg, Vincent;  Moris, Naomi;  Blotenburg, Marloes;  Vivie, Judith;  Baillie-Johnson, Peter;  Nichols, Jennifer;  Sonnen, Katharina F.;  Martinez Arias, Alfonso;  van Oudenaarden, Alexander
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

An automated synthesis instrument comprising a series of continuous flow modules that are radially arranged around a central switching station can achieve both linear and convergent syntheses.


Automated synthesis platforms accelerate and simplify the preparation of molecules by removing the physical barriers to organic synthesis. This provides unrestricted access to biopolymers and small molecules via reproducible and directly comparable chemical processes. Current automated multistep syntheses rely on either iterative(1-4) or linear processes(5-9), and require compromises in terms of versatility and the use of equipment. Here we report an approach towards the automated synthesis of small molecules, based on a series of continuous flow modules that are radially arranged around a central switching station. Using this approach, concise volumes can be exposed to any reaction conditions required for a desired transformation. Sequential, non-simultaneous reactions can be combined to perform multistep processes, enabling the use of variable flow rates, reuse of reactors under different conditions, and the storage of intermediates. This fully automated instrument is capable of both linear and convergent syntheses and does not require manual reconfiguration between different processes. The capabilities of this approach are demonstrated by performing optimizations and multistep syntheses of targets, varying concentrations via inline dilutions, exploring several strategies for the multistep synthesis of the anticonvulsant drug rufinamide(10), synthesizing eighteen compounds of two derivative libraries that are prepared using different reaction pathways and chemistries, and using the same reagents to perform metallaphotoredox carbon-nitrogen cross-couplings(11) in a photochemical module-all without instrument reconfiguration.


  
A bioorthogonal system reveals antitumour immune function of pyroptosis 期刊论文
NATURE, 2020
作者:  Kim, Sungchul;  Loeff, Luuk;  Colombo, Sabina;  Jergic, Slobodan;  Brouns, Stan J. J.;  Joo, Chirlmin
收藏  |  浏览/下载:49/0  |  提交时间:2020/07/03

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis(1-5). Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and '  cleaves'  a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology  our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.


In mouse models of cancer, a biorthogonal chemical system based on desilylation catalysed by phenylalanine trifluoroborate enables the controlled release of gasdermin to induce pyroptosis selectively in tumour cells


  
Synthesis of rare sugar isomers through site-selective epimerization 期刊论文
NATURE, 2020: 403-+
作者:  Jackson, Hartland W.;  Fischer, Jana R.;  Zanotelli, Vito R. T.;  Ali, H. Raza;  Mechera, Robert;  Soysal, Savas D.;  Moch, Holger;  Muenst, Simone;  Varga, Zsuzsanna;  Weber, Walter P.;  Bodenmiller, Bernd
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

Glycans have diverse physiological functions, ranging from energy storage and structural integrity to cell signalling and the regulation of intracellular processes(1). Although biomass-derived carbohydrates (such as d-glucose, d-xylose and d-galactose) are extracted on commercial scales, and serve as renewable chemical feedstocks and building blocks(2,3), there are hundreds of distinct monosaccharides that typically cannot be isolated from their natural sources and must instead be prepared through multistep chemical or enzymatic syntheses(4,5). These '  rare'  sugars feature prominently in bioactive natural products and pharmaceuticals, including antiviral, antibacterial, anticancer and cardiac drugs(6,7). Here we report the preparation of rare sugar isomers directly from biomass carbohydrates through site-selective epimerization reactions. Mechanistic studies establish that these reactions proceed under kinetic control, through sequential steps of hydrogen-atom abstraction and hydrogen-atom donation mediated by two distinct catalysts. This synthetic strategy provides concise and potentially extensive access to this valuable class of natural compounds.


Various rare sugars that cannot be isolated from natural sources are synthesized using light-driven epimerization, a process which may find application in other synthetic scenarios.


  
The impact of relative humidity on the size distribution and chemical processes of major water-soluble inorganic ions in the megacity of Chongqing, China 期刊论文
ATMOSPHERIC RESEARCH, 2017, 192
作者:  Wang, Lu;  Ji, Dongsheng;  Li, Yi;  Gao, Meng;  Tian, Shili;  Wen, Tianxue;  Liu, Zirui;  Wang, Lili;  Xu, Peng;  Jiang, Changsheng;  Wang, Yuesi
收藏  |  浏览/下载:5/0  |  提交时间:2019/04/09
Relative humidity  Size distribution  Water-soluble inorganic ions  Chemical processes  Chongqing