125184-95-4

Usage

Uses

1. Used in Pharmaceutical Industry:
Dehydroartemisinyl alcohol is used as a precursor for the semi-synthesis of artemisinin (A777500) for its potent antimalarial properties. Artemisinin is an effective agent used to treat malaria, a disease caused by parasites that infect red blood cells.
2. Used in Antimalarial Applications:
Dehydroartemisinyl alcohol is utilized as a key compound in the production of artemisinin, which serves as an antimalarial agent. It is particularly effective against Plasmodium parasites responsible for causing malaria, offering a vital treatment option for individuals suffering from this life-threatening disease.
3. Used in Drug Development:
As a precursor to artemisinin, dehydroartemisinyl alcohol is essential in the development of new drugs and therapies targeting malaria. Its role in the semi-synthesis of artemisinin highlights its importance in the pharmaceutical industry, where it contributes to the creation of innovative and effective treatments for this global health issue.

Upstream product

• 92692-39-2 (1R,4R,4aS,8aR)-4,7-dimethyl-1-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene 
• 80286-58-4 artemisinic acid 
• 186581-53-3 diazomethane 
• 76-05-1 trifluoroacetic acid 
• 593-71-5 Chloroiodomethane 
• 917-54-4 methyllithium 
• 64-17-5 ethanol 
• 916311-23-4 amorphadiene-11,12-epoxide 
• 82869-24-7 methyl artemisinate 

Downstream Products

• 80286-58-4 artemisinic acid 
• 125276-60-0 artemisinic aldehyde 

Relevant academic research and scientific papers

Palladium-Catalyzed Regioselective Allylic Oxidation of Amorphadiene, a Precursor of Artemisinin

A regioselective Pd-catalyzed allylic oxidation of amorphadiene, a key precursor to the antimalarial drug artemisinin, is described. Amorphadiene can be obtained in high yields by fermentation, but it is currently treated as a waste in the industrial semisynthetic artemisinin process. The catalytic step described here is a substitute for the P450 enzymes involved in the artemisinin biosynthesis and opens up new opportunities to supplement a critical step in the current semisynthetic route and increase the potential of the fermentation process.

An enantioselective ambimodal cross-Diels–Alder reaction and applications in synthesis

Compared with the conventional Diels–Alder reaction, the development of selective cross-Diels–Alder reactions between two different conjugated dienes, especially in a catalytic asymmetric manner, has been neglected. We now report a peri- and enantioselective cross-Diels–Alder reaction of 3-alkoxycarbonyl-2-pyrones with unactivated conjugated dienes catalysed by a copper(II)–bis(oxazoline) complex, leading to formal inverse-electron-demand adducts with high enantioselectivity under mild reaction conditions. Computational studies showed that this reaction proceeds through an ambimodal transition state: post-transition-state bifurcation leads to [2+4] and [4+2] adducts with the same enantioselectivity, followed by a facile Cope rearrangement to provide a single observed thermodynamic [2+4] product. This reaction occurs with a wide variety of cyclopentadienes, fulvenes and cyclohexadienes, providing a highly efficient and enantioselective approach to densely functionalized cis-bicyclic scaffolds. The synthetic value of this reaction is demonstrated by the asymmetric synthesis of two biologically important natural products, artemisinic acid and coronafacic acid. [Figure not available: see fulltext.].

High-level semi-synthetic production of the potent antimalarial artemisinin

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

POLYNUCLEOTIDES ENCODING ISOPRENOID MODIFYING ENZYMES AND METHODS OF USE THEREOF

The present invention provides isolated nucleic acids comprising nucleotide sequences encoding isoprenoid modifying enzymes, as well as recombinant vectors comprising the nucleic acids. The present invention further provides genetically modified host cells comprising a subject nucleic acid or recombinant vector. The present invention further provides a transgenic plant comprising a subject nucleic acid. The present invention further provides methods of producing an isoprenoid compound, the method generally involving culturing a subject genetically modified host cell under conditions that permit synthesis of an isoprenoid compound modifying enzyme encoded by a subject nucleic acid.

CONVERSION OF AMORPHA-4,11-DIENE TO ARTEMISININ AND ARTEMISININ PRECURSORS

The present invention relates to methods for the conversion of amorpha-4,11-diene to artemisinin and various artemisinin precursors.

Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua

An important group of antimalarial drugs consists of the endoperoxide sesquiterpene lactone artemisinin and its derivatives. Only little is known about the biosynthesis of artemisinin in Artemisia annua L., particularly about the early enzymatic steps between amorpha-4,11-diene and dihydroartemisinic acid. Analyses of the terpenoids from A. annua leaves and gland secretory cells revealed the presence of the oxygenated amorpha-4,11-diene derivatives artemisinic alcohol, dihydroartemisinic alcohol, artemisinic aldehyde, dihydroartemisinic aldehyde and dihydroartemisinic acid. We also demonstrated the presence of a number of biosynthetic enzymes such as the amorpha-4,11-diene synthase and the - so far unknown - amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes. From these results, we hypothesise that the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation to artemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinic aldehyde and oxidation to dihydroartemisinic acid.

Antimalarial activities of (+)-deoxoartemisitene and its novel C-11, 13 derivatives

(+)-Deoxoartemisitene and its C-11, 13 derivatives were synthesized from artemisinic acid via a short and regiospecific process and several derivatives show 10-20 times more in vitro antimalarial activities against Plasmodium falciparum than artemisinin.

Hydroxylation of sesquiterpenes by enzymes from chicory (Cichorium intybus L.) roots

A microsomal enzyme preparation of chicory roots catalyses the hydroxylation of various sesquiterpene olefins in the presence of NADPH. Most of these hydroxylations take place at an isopropenyl or isopropylidene group. The number of products obtained from any of the substrates is confined to one or, in a few cases, two sesquiterpene alcohols. In addition, the conversion of (+)-valencene into nootkatone through β-nootkatol was observed. The involvement of (+)-germacrene A hydroxylase (a cytochrome P450 enzyme) and other enzymes of sesquiterpene lactone biosynthesis in these reactions is discussed.

First synthesis of (+)-deoxoartemisitene and its novel C-11 derivatives

A short, regiospecific and first synthesis of (+)-deoxoartemisitene and its novel C-11 derivatives with non-acetal at C-12 was achieved from artemisinic acid.