Synthesis of C-Alkynyl Glycosides by Photoredox-Catalyzed Reductive Coupling of Alkynyl Bromides with Glycosyl Bromides.

A general, convenient, and highly α stereoselective approach to access C-alkynyl glycosides via the photoredox-catalyzed reductive coupling of alkynyl bromides and glycoside bromides has been developed. Cheap and small-load eosin Y is used as the photocatalyst, and organic base N,N-diisopropylethylamine serves as the reducing reagent. This strategy features readily available starting materials, diverse substrates, mild conditions, and high α stereoselectivity. Moreover, a glycoconjugated peptide could also be achieved using this strategy.

Triazol: a privileged scaffold for proteolysis targeting chimeras.

Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer activity. This review provides an overview of PROTACs with a triazole scaffold and discusses its structure-activity relationship. Important milestones in the development of PROTACs are addressed and a critical analysis of this drug discovery strategy is also presented.

The Present and Future of Novel Protein Degradation Technology.

Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs technology, is now receiving more attention. In this review, we aim to summarize the rapid progress from 2018 to 2019 in protein degradation and analyze the challenges and future direction that need to be addressed in order to efficiently develop potent protein degradation technology.

Concise synthesis of 2-methoxyestradiol from 17ß-estradiol through the C(sp2)-H hydroxylation.

A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17ß-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p-cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5).

Design, synthesis and antiproliferative effect of 17ß-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics.

A series of 17ß-amide-2-methoxyestradiol compounds were synthesized with an aim to enhance the antiproliferative effect of 2-methoxyestradiol. The antiproliferative activity of 2-methoxyestradiol analogs against human cancer cells was investigated. 2-methoxy-3-benzyloxy-17ß-chloroacetamide-1,3,5(10)-triene (5e) and 2-methoxy-3-hydroxy-17ß-butyramide-1,3,5(10)-triene (6c) had comparable or better antitumor activity than 2-methoxyestradiol. The elimination half-life of 6c (t1/2ß=240.93min) is ten times longer than 2-ME and the area under the curve was seven times (AUC0-tmin=2068.20±315.74µgmL-1min) higher than 2-ME, respectively. Whereas 5e had similar pharmacokinetic behavior with 2-ME (t1/2ß=22.28min) with a t1/2ß of 29.5 min. 6c had higher blood concentration, longer actuation duration and better suppression rate against S180 mouse ascites tumor than 2-methoxyestradiol.

[Seasonal Effect of Simulated Nitrogen Deposition on Soil Respiration and Soil Enzyme Activity in Masson Pine Forest in Mt. Jinyun, Chongqing, China].

Soil enzymes involved in the conversion of soil carbon and nitrogen, meanwhile the availability of soil carbon and nitrogen is the base of soil enzymes, yet atmospheric N deposition influences the release of soil CO2 by reduce the activities of soil enzyme. The objective of this study was to investigate the effect of different nitrogen deposition on soil respiration and soil enzymes, and explore the relationship among soil respiration, soil temperature, soil moisture and soil enzymes in the Masson pine forest. The results might provide a reference for further study on the effects of nitrogen deposition on pine forest ecosystem. From May 2014 to July 2015, three nitrogen application treatments and a control treatment were set up: low nitrogen [N5, 20 g·(m2·a)-1], moderate nitrogen [N10, 40 g·(m2·a)-1], high nitrogen [N15, 60 g·(m2·a)-1] and control treatment [N0, 0 g·(m2·a)-1) in the Masson pine forest. We measured soil respiration, soil temperature, and soil moisture simultaneously by using the Automated Soil CO2 Exchange Station (ACE, UK). The results showed that: 1 Soil enzymes and soil respiration had obvious seasonal variation, soil respiration of N0, N5, N10 and N15 was the highest in Summer, followed by the Spring and Autumn, and the lowest in Winter, and no consistent change rule was found in soil enzymes. 2 Generally, nitrogen deposition suppressed soil respiration and soil enzymes, and these inhibitory effects were strengthened with increasing levels of nitrogen deposition. The only exception in which nitrogen deposition enhanced soil respiration was in the Masson pine forest in Winter, In Spring, Summer and Autumn, nitrogen deposition suppressed soil enzymes, while there was difference among Ure, Ive, CAT and ACP in Winter. 3 stepwise regression showed that in control treatment and low nitrogen treatment, T, Ure and Ive made great contributions to the Rs, and Rs rapidly increased with the increase of T, Ure and Ive. In middle nitrogen treatment, T, Ure and CAT made great contributions to the Rs, and Rs increased with the increase of T, Ure and CAT. In high nitrogen treatment, Rs decreased with the increase of Ure, yet Rs increased with the increase of CAT and W.