Development of a Pilot Scale Process for the Anti-Alzheimer Drug (−)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion

Küenburg, Bernhard; Czollner, Laszlo; Fröhlich, Johannes; Jordis, Ulrich

doi:10.1021/op990019q

Cited by 110 publications

(95 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Various syntheses had been reported [first by Barton and Kirby (Barton and Kirby, 1962)] before a kilogram scale route was developed to allow the industrial production of galanthamine hydrobromide by chemical means [ Fig. 5; (Czollner et al, 2000;Küenburg et al, 1999)]. …”

Section: Organic Synthesismentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

Draw Science

View full text Add to dashboard Cite

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

show abstract

Section: Organic Synthesismentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

Draw Science

View full text Add to dashboard Cite

show abstract

“…1), which dehydrates to form an imine (Schiff base) or iminium ion 2, and the reduction of 2 produces the alkylated amine 3 (Abdel-Magid et al, 1996). Because of one-pot reaction, mild reaction conditions, and use of eco-friendly reagents, the reaction is widely used in the preparation of different kinds of amines such as natural products, drugs, and agrochemicals (Guo and O′Doherty, 2008;Küenburg et al, 1999;Liu et al, 2009;Posner, 1986), and is also ideally suitable for generating molecular diversity since it provides rapid and general access to C-N bond (Dinsmore and Zartman, 2000;Lev et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

A facile synthesis of 2-aryloxypyrimidine derivatives via a tandem reductive amination/intermolecular SNAr sequence

Zhang

2010

J. Zhejiang Univ. Sci. B

View full text Add to dashboard Cite

Abstract:A novel tandem reductive amination/intermolecular nucleophilic aromatic substitution (S N Ar) sequence has been established for the synthesis of amine containing pyrimidine in formation of one carbon-oxygen and one carbon-nitrogen bonds in a one-pot fashion. Treatment of aldehyde with arylamine, 2-methanesulfonyl-4,6-dimethoxypyrimidine and sodium borohydride provides good overall yield. The p-toluenesulfonic acid (PTSA) can be used as activator and is generally needed in the reaction. Dioxane is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran (THF), MeCN, toluene and dichloromethane. The procedure is carried out effectively in the presence of K 2 CO 3 . The reaction proceeds smoothly with aromatic aldehydes and arylamines possessing electron-donating or -withdrawing groups. This method can be applied to the synthesis of the oilseed rape herbicide and is superior to the classical one in several aspects: cutting out several purification steps, minimizing solvent use and chemical waste, and saving time. Its advantages such as operational convenience, high-efficient synthesis, and starting material availability make it a desirable method for preparing amines with molecular diversity and biological activity.

show abstract

“…Because galanthamine (GAL) is an important drug for the symptomatic treatment of senile dementia or Alzheimer's disease (AD), it is the most newly promising AChE inhibitor -in the USA by the Food and Drug Administration and in Europe by the European Registration Bureau (Howes et al, 2003;LaurainMattar, 2008). For many years a lot of research effort was spent to synthesize GAL (Czollner et al, 1998;Parsons et al, 2001;Herlem et al, 2003;Küenburg et al, 1999), but the total organic synthesis of GAL is complicated and thus expensive. Meanwhile much research has been done to fi nd new ways to produce GAL by biological technology, for example by adding exogenous growth regulators during organogenesis and somatic embryogenesis (Colque et al, 2004) and transformation of Leucojum aestivum L. using Agrobacterium rhizogenes to form hairy root cultures (Diop et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Effect of Abiotic and Biotic Elicitors on Growth and Alkaloid Accumulation of Lycoris chinensis Seedlings

Ren

et al. 2009

Zeitschrift Für Naturforschung C

View full text Add to dashboard Cite

Three-month-old seedlings of Lycoris chinensis were treated with biotic and abiotic elicitors: yeast elicitor (YE), methyl jasmonate (MJ), salicylic acid (SA), and sodium nitroprusside as NO donator (NO). We have shown that the addition of MJ and NO promotes the accumulation of galanthamine in these seedlings. The effect of these elicitors on the growth of the seedlings, as well as on the amount of the alkaloids accumulated in the seedlings was studied. The results showed that, in general, high doses of MJ and SA had a negative effect on the growth of the seedlings, while appropriate doses of NO and YE had a positive effect on the growth of the seedlings. It was remarkable that the addition of MJ, NO, and YE can promote galanthamine accumulation in seedlings. The accumulation was higher in treatments at higher concentrations of NO (100 µM), where the release of galanthamine was 1.72-fold higher than that of the control at the 10 th day of culture. The highest values of lycorine were obtained in seedlings treated with YE at a concentration of 0.01 g/l and by the 10 th day of culture; the level was 1.38 times of the control.

show abstract

Development of a Pilot Scale Process for the Anti-Alzheimer Drug (−)-Galanthamine Using Large-Scale Phenolic Oxidative Coupling and Crystallisation-Induced Chiral Conversion

Cited by 110 publications

References 18 publications

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Discovery and resupply of pharmacologically active plant-derived natural products: A review

A facile synthesis of 2-aryloxypyrimidine derivatives via a tandem reductive amination/intermolecular SNAr sequence

Effect of Abiotic and Biotic Elicitors on Growth and Alkaloid Accumulation of Lycoris chinensis Seedlings

Contact Info

Product

Resources

About