- Short and efficient syntheses of protoberberine alkaloids using palladium-catalyzed enolate arylation
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A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladiumcatalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50%is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine-containing derivative synthesized here.
- Gatland, Alice E.,Pilgrim, Ben S.,Procopiou, Panayiotis A.,Donohoe, Timothy J.
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- Modular and Divergent Syntheses of Protoberberine and Protonitidine Alkaloids
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A modularly convergent and divergent strategy was established for the family synthesis of both protoberberine and protonitidine alkaloids. The robust, scalable, and flexible synthetic route featured a collective preparation of protoberberine and protonitidine alkaloids from a common isoquinoline assembled from pyridyne as the key synthon, which was based on the selective N-C or C-C cyclization via distinct processes. Through the strategy, 20 protoberberine alkaloids, 5 protonitidine alkaloids, and 11 analogues with diverse substituents were comprehensively aquired.
- Liu, Kai,Jiang, Xuefeng
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- Highly efficient synthesis and monoamine oxidase B inhibitory profile of demethyleneberberine, columbamine and palmatine
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The biosynthesis of berberine alkaloids is thought to begin with the demethylation of berberine followed by methylation reactions to generate other type berberine alkaloids. This seemingly expeditious way to access berberine alkaloids has been stagnated for over half a century due to certain vexing synthetic problems, such as low isolated yield, complex operations and toxic reagents. We further investigated this bioinspired semi-synthesis strategy and significantly improved the synthetic efficacy, by providing a practical synthetic process for demethyleneberberine (DMB), columbamine and palmatine. Furthermore, we found that DMB (IC50, 9.06 μM) inhibited the activity of monoamine oxidase B (MAO-B), an enzyme that deaminates dopamine and is particularly involved in the pathology of Parkinson's disease. Besides, columbamine was able to decrease MAO-B activity by approximately 40%. These findings provide perquisites for further in vivo investigation to confirm the therapeutic potentiality of berberine alkaloids, DMB in particular.
- Chen, Jian,Chen, Yuan-ji,Cui, Guo-zhen,Hu, Sheng-quan,Ma, Min,Sun, Ke-huan,Tao, Cheng,Wu, Zheng-zhi
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- Cobalt-Mediated Decarboxylative/Desilylative C?H Activation/Annulation Reaction: An Efficient Approach to Natural Alkaloids and New Structural Analogues
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A Co(II)-mediated decarboxylative/desilylative C?H activation/annulation reaction for the efficient synthesis of 3-arylisoquinolines has been developed. Using alkynyl carboxylic acid and alkynyl silane as terminal alkyne precursors, providing straightforw
- Hai, Li,Lai, Ruizhi,Lv, Shan,Nie, Ruifang,Wu, Yong,Yang, Zhongzhen,chen, Kang
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- Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as the RXRα Activator to Inhibit Colon Cancer
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We reported recently that berberine (Ber), a traditional oriental medicine to treat gastroenteritis, binds and activates retinoid X receptor α (RXRα) for suppressing the growth of colon cancer cells. Here, we extended our studies based on the binding mode of Ber with RXRα by design, synthesis, and biological evaluation of a focused library of 15 novel Ber analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently than Ber, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing the Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved Ber's tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 did not show obvious side effects including hypertriglyceridemia as other RXRα agonists or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of Ber-derived RXRα activators as novel effective antineoplastic agents for colon cancer.
- Xu, Beibei,Jiang, Xunjin,Xiong, Jing,Lan, Jun,Tian, Yuan,Zhong, Linhai,Wang, Xinquan,Xu, Ning,Cao, Hanwei,Zhang, Wenqing,Zhang, Hao,Hong, Xiaoting,Zhan, Yan-Yan,Zhang, Yandong,Hu, Tianhui
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p. 5841 - 5855
(2020/07/03)
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- Water-mediated C-H activation of arenes with secure carbene precursors: The reaction and its application
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A water-mediated C-H activation using sulfoxonium ylides is reported, providing a general, green and step-economic approach to construct a C-C bond and varieties of useful N-heterocycle scaffolds. Notably, the "water-mediated" activation, in contrast to that in organic solvents, shows great potential in pharmaceutical, biochemistry and chemical industries.
- Guo, Li,Lai, Ruizhi,Lv, Songyang,Nie, Ruifang,Wang, Qiantao,Wu, Yong,Xu, Yingying
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p. 11418 - 11421
(2019/09/30)
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- Preparation method of palmatine hydrochloride
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The invention discloses a preparation method of palmatine hydrochloride. By adopting a method for synthesizing palmatine hydrochloride from berberine hydrochloride, damage to plant resources caused byextraction of the palmatine hydrochloride from plants and the environmental pollution caused by the use of a large amount of sulfuric acid in an extraction process can be avoided, and the ecologicalenvironment is protected. The preparation method has the advantages of adoption of cheap and readily-available reaction raw materials, avoidance of the use of highly-toxic conventional methylation reagent dimethyl sulfate or iodomethane or bromomethane, short synthetic route, easiness in operation and suitability for industrial production.
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Paragraph 0008; 0017; 0019; 0020; 0021; 0023; 0024
(2018/10/11)
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- A room-temperature protocol to access isoquinolines through Ag(i) catalysed annulation of o-(1-alkynyl)arylaldehydes and ketones with NH4OAc: Elaboration to berberine and palmatine
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An efficient and mild protocol for the direct construction of aryl- and alkyl-substituted isoquinolines has been realized through silver nitrate catalyzed aromatic annulation of o-(1-alkynyl)arylaldehydes and ketones with ammonium acetate. The salient feature of this methodology is that this annulation could be effected at room temperature leading to a wide range of isoquinoline derivatives in good to excellent yields. Additionally, this approach has been employed to the synthesis of biologically important isoquinoline alkaloids such as berberine and palmatine.
- Reddy, Virsinha,Jadhav, Abhijeet S.,Vijaya Anand, Ramasamy
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p. 3732 - 3741
(2015/03/30)
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