Synthesis of Withanolide A, Biological Evaluation of Its Neuritogenic Properties, and Studies on Secretase Inhibition

Jana, Chandan K.; Hoecker, Johannes; Woods, Tom M.; Jessen, Henning J.; Neuburger, Markus; Gademann, Karl

doi:10.1002/anie.201101869

Cited by 54 publications

(34 citation statements)

References 39 publications

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“…We have synthesized withanolide A (Fig. 4), [28] which has been shown by Tohda et al to facilitate neurite outgrowth and synapse reconstruction, [29] and have evaluated its biological properties and mechanism of action by cellular and enzymatic studies. In fact, withanolide A was able to induce neuritogenesis in SY5Y cells, these effects, however, were conditional to the use of medium and surface coating of wells.…”

Section: Sb640mentioning

confidence: 99%

“…In fact, withanolide A was able to induce neuritogenesis in SY5Y cells, these effects, however, were conditional to the use of medium and surface coating of wells. [28] Another class of compounds displaying neuritogenic properties are phenylpyridone alkaloids, [30] some of which have originally been isolated by Hamburger and coworkers. [31] We have developed a unified synthetic approach to this class of compounds and have prepared several natural products and putative natural products that have not (yet) been identified.…”

Section: Sb640mentioning

confidence: 99%

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Chemical Interference of Biological Systems with Natural Products

Gademann¹,

Sieber²

2011

Chimia

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Chemical compounds isolated from natural sources offer unique opportunities to understand life on a molecular level. In this account, an overview over different natural products investigated in our research group over the last decade is presented. We have shown that protein localization in living cells can be controlled by anguinomycins and derivatives. Furthermore, a truncated analog, SB640, was discovered that retained much of the natural product potency. Detailed studies of the iron chelator anachelin led to the development of a bio-inspired platform for the generation of bioactive interfaces. The discovery of natural products isolated from cyanobacteria such as nostocarboline, aerucyclamides, cyanopetolin 1020 and various microcystins is presented and their molecular mechanisms of action were investigated. The last part describes the synthesis and evaluation of various natural products involved in neuritogenesis and synapse reconstruction such as withanolide A, militarinone, farinosone A and C and torrubiellone C. Their potential with regard to their use in regenerative medicine is discussed.

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Section: Sb640mentioning

confidence: 99%

Section: Sb640mentioning

confidence: 99%

Chemical Interference of Biological Systems with Natural Products

Gademann¹,

Sieber²

2011

Chimia

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“…Historically, another approach, which relies on the innate reactivity profile of the framework in the absence of a directing template, has also been widely employed, as evidenced by the wealth of synthesis literature on terpene functionalizations (3, 4). Use of this approach has enabled semi-syntheses of highly complex steroids such as digitoxin (5), batrachotoxin (6), dihydroconessine (7), cyclopamine (8), cortistatin A (9), and withanolide A (10) and has laid a foundation for pharmaceutical research on commercial semi-synthetic steroid medicines such as finasteride, dexamethasone, and progestin. Despite these achievements, the scalable synthesis of polyhydroxylated steroids (more than five hydroxyl moieties on the tetracyclic skeleton, Figure 1B) is rare.…”

mentioning

confidence: 99%

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Renata

Zhou

Baran

2013

Science

160

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Here we report a scalable route to the polyhydroxylated steroid ouabagenin with an unusual spin on the age-old practice of steroid semi-synthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 mg of a key precursor towards ouabagenin–and ultimately ouabagenin itself–and the discovery of innovative methods for C–H and C–C activation and C–O bond hemolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules.

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“…Such a low abundance is incapable of meeting the present economic demand for medicinal formulations. In this regard, chemical synthesis of these plant natural products were attempted, however, sheer structural complexity and the specific stereochemical requirements of the compounds resulted in their low yield (Jana et al 2011). Plant cell cultures had been set up as an alternative for extraction of SMs which ended up in limited commercial success and technological issues such as maintenance of large bioreactors and cultivation conditions (Oksman-Caldentey and Inze 2004).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of squalene synthase in Withania somnifera leads to enhanced withanolide biosynthesis

Patel

Kendurkar

et al. 2015

Plant Cell Tiss Organ Cult

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Genetic engineering of secondary metabolic pathways is an emerging area of research for production and improvement of natural products in plant biotechnology. Here, we describe a systematic approach to manipulate a key regulatory step of isoprenoid biosynthetic pathway in Withania somnifera to study its effect on withanolide production. We generated T 0 W. somnifera plants overexpressing squalene synthase (WsSQS) by Agrobacterium tumefaciens mediated transformation, which were analyzed by Gus biochemical assay and PCR of hygromycin phosphotransferase (hptII) and WsSQS. qRT-PCR analyses of various transformed tissues indicated 2-5 fold increase in WsSQS transcripts in both T 0 and T 1 generations. The tissue specific protein expression studies revealed 2-3 fold increase in WsSQS, which was further confirmed by enzyme activity. These observations were corroborated with the 1.5-2 fold increase in total withanolide content of the transformed tissues. However, in leaf tissue, the levels of Withaferin A and Withanolide A increased significantly up to 4-4.5 fold. These findings demonstrate genetic engineering of isoprenoid pathway in W. somnifera resulting in enhanced production of withanolides, and also provide insights into such metabolic pathways for their manipulation to improve the pharmacological content of different medicinally important plants.

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Synthesis of Withanolide A, Biological Evaluation of Its Neuritogenic Properties, and Studies on Secretase Inhibition

Cited by 54 publications

References 39 publications

Chemical Interference of Biological Systems with Natural Products

Chemical Interference of Biological Systems with Natural Products

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Overexpression of squalene synthase in Withania somnifera leads to enhanced withanolide biosynthesis

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