Transformation of artemisinin by Cunninghamella elegans

Abstract

Semi-synthetic derivatives of the anti-malarial drug artemisinin hold great promise in the search for an effective and economical treatment of chloroquine-resistant forms of malaria. Unfortunately, synthetic functionalization of the artemisinin skeleton is often tedious and/or impractical. We seek to utilize 7beta-hydroxyartemisinin, obtained from microbial transformation, as a semi-synthetic precursor for the synthesis of novel 7beta-substituted artemisinin anti-malarial agents. Here we employ liquid cultures of Cunninghamella elegans as a means for the rational and economical bioconversion of artemisinin to 7beta-hydroxyartemisinin in 78.6% yield. In addition, there were three other bioconversion products: 7beta-hydroxy-9alpha-artemisinin (6.0%), 4alpha-hydroxy-1-deoxoartemisinin (5.4%), and 6beta-hydroxyartemisinin (6.5%).

Biotransformation of artemisinin by Aspergillus niger

“…The comparison of the 1 H NMR data of metabolite 5 with those of 4α-hydroxy-1-deoxyartemisinin (Parshikov et al 2004b) was in complete agreement. Therefore, metabolite 5 was confirmed to be 4α-hydroxy-1-deoxyartemisinin (Fig.…”

“…There are many reports on microbial transformation of artemisinin. These transformations usually include the following metabolic processes: hydroxylation, deoxidation, and acetoxylation reactions (Gaur et al 2014;Parshikov et al 2004bParshikov et al , 2006Zhan et al 2002;Goswami et al 2010). The products of the reported microbial transformations of artemisinin usually include 7β-hydroxyartemisinin, 7β-hydroxy-9α-artemisinin, 4α-hydroxy-1-deoxyartemisinin, 6β-hydroxyartemisinin, 5β-h y d r o x y a r t e m i s i n i n , 4 β -h y d r o x y a r t e m i s i n i n , deoxyartemisinin, 4β-hydroxy-1-deoxyartemisinin, 5aα-hydroxy-1-deoxyartemisinin, 4β-acetoxy artemisinin, 4α-hydroxyartemisinin, and 5aα-hydroxyartemisinin (Parshikov et al 2004b(Parshikov et al , 2006Zhan et al 2002;Goswami et al 2010;Gaur et al 2014).…”

Biotransformation of Artemisinin Mediated through Fungal Strains for Obtaining Derivatives with Novel Activities

“…Studies on the microbial transformation of artemisinin with Nocardia corollina, Penicillium chrysogenum, Mucor polymorphus, Cunninghamella echinulata, Mucor ramannianus, Eurotium amstelodami, Streptomgillus niger, Cunninghamella elegans yielded 3α-hydroxydeoxyartemisinin, deoxyartemisinin, artemisitone-9, 4α-hydroxyartemisinin, 7β-hydroxyartemisinin, 6-hydroxyartemisinin, 5β-hydroxyartemisinin, 9β-hydroxyartemisinin, 3β-hydroxyartemisinin, 3β-hydroxydeoxyartemisinin, 1α-hydroxydeoxyartemisinin, 7β-hydroxy-9α-artemisinin, 4α-hydroxy-1-deoxoartemisinin, 10β-hydroxyartemisinin and 3α-hydroxydeoxyartemisinin respectively [4,[15][16][17][18][19][20]. The importance and usefulness of microbial transformation in carrying out a variety of chemical conversions is well documented in the previously published reports [21,22].…”

Microbial transformation of artemisinin to 5-hydroxyartemisinin by Eurotium amstelodami and Aspergillus niger

“…Cultures and controls were incubated at 28°C in environmental shakers. Wellgrown cultures were harvested after 14 days and extracted exhaustively with ethyl acetate and evaporated to dryness [5].…”

“…To date microbial transformation methodologies have been developed to efficiently and selectively derivatize a number of pharmacologically important positions on the artemisinin skeleton, positions that otherwise require inefficient synthetic derivatization. Biotransformations have been used to selectively hydroxylate the four-position [3][4][5], the six-position [3,5], and the seven-position [4][5][6] of artemisinin. Here, we report the biotransformation of artemisinin by Eurotium amstelodami and Aspergillus niger to the novel 5-hydroxyartemisinin derivative.…”