Baeyer-Villiger Oxidation of Some C19 Steroids by Penicillium lanosocoeruleum

Abstract

Abstract:The biotransformation of androsterone (1), epiandrosterone (2), androstanedione (3) and DHEA (dehydroepiandrosterone) (4) by Penicillium lanosocoeruleum-a fungal species not used in biotransformations so far-were described. All the substrates were converted in high yield (70%-99%) into D ring δ-lactones. The oxidation of 1 produced 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5). The oxidation of 2 led to 3β-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (6). The biotransformation of 3 resulted in the formation of 3α-hydroxy-17a-oxa-D-homo-5α-androstan-17-one (5) and 17a-oxa-Dhomo-5α-androstan-3,17-dione (7). An analysis of the transformation progress of the studied substrates as a function of time indicates that the Baeyer-Villiger monooxygenase of this fungus does not accept the 3β-hydroxy-5-ene functionality of steroids. In this microorganism steroidal 3β-hydroxy-dehydrogenase (3β-HSD) was active, and as a result DHEA (4) was transformed exclusively to testololactone (8). Apart from the observed oxidative transformations, a reductive pathway was revealed with the C-3 ketone being reduced to a C-3α-alcohol. It is demonstrated for the first time that the reduction of the 3-keto group of the steroid nucleus can occur in the presence of a ring-D lactone functionality.

Biotransformation of dehydroepiandrosterone (DHEA) by environmental strains of filamentous fungi

“…DHEA may be transformed directly to 3bOH-lactone: Penicillium lilacinum AM111, Aspergillus tamarii KITA; 42,43 2. At rst isomerization and oxidation of 3-hydroxy-5-ene moiety to 3-oxo-4-ene occure, and then BV oxidation of the D ring takes place -Penicillium griseopurpureum, Penicillium lanosocoeruleum; 44,45 3. At rst BV oxidation to 3bOH-lactone occurs and then oxidation of the hydroxyl group at C-3 takes place, leading to formation of testololactone: Penicillium simplicissimum WY134-2, Aspergillus parasitic.…”

Microbial Modifications of Androstane and Androstene Steroids by Penicillium vinaceum

“…Our earlier studies with biotransformations of steroids by the fungi of genus Penicillium [ 31 , 32 , 35 , 36 ] have revealed large diversity of metabolic fates of the substrates. Baeyer-Villiger oxidation, isomerizations, and hydroxylations with diverse product stereochemistry were found.…”

“…Such an idea of configurational flexibility of steroid substrates was proposed already in 1967 on the basis of diverse metabolic fates of steroids biotransformed by Aspergillus tamarii cultures [ 28 ]. Some recent examples of the presence of steroidal BVMOs in fungal biotransformation pathways are: lactonization of progesterone and 5-ene steroids [ 29 , 30 ]; lactonization of dehydroepiandrosterone (DHEA), pregnenolone, and androstenedione by filamentous fungi of genus Penicillium [ 31 , 32 ]; lactonization of DHEA by Aspergillus parasiticus [ 33 ]; ring- d lactonization of steroidal C-17 ketones to 11α-hydroxy derivatives by Beauveria bassiana [ 34 ]; activity of Penicillium lanosocoeruleum in ring- d lactonization of C 19 -steroids [ 35 ] and pregnene-based steroids [ 36 ]; biotransformation of DHEA into hydroxylated steroid lactones Spicaria fumoso-rosea [ 37 ]; diverse biotransformation routes of steroids, including ring- d lactonization, in the cultures of Penicillium notatum [ 24 ] and Aspergillus terreus [ 38 ]; formation of testololactone from diverse steroidal substrates with the use of a multifunctional strain of Penicillium simplicissimum [ 39 ]; cascade of DHEA biotransformations by Beauveria species [ 40 ]; and the formation of new derivatives of 3β-acetyloxy-5α-chloro-6,19-oxidoandrostan-17-one [ 41 ]. This rich background of BVMO activity studies in fungal species, combined with the outlined above need for further research in the field of biotransformations, prompted us to investigate in detail metabolic fates of DHEA ( 1 ), epiandrosterone ( 2 ), androsterone ( 3 ), androstenedione ( 4 ), 19-OH-androstenedione ( 5 ), testosterone ( 6 ), 19-nortestosterone ( 7 ), progesterone ( 8 ), and pregnenolone ( 9 ) in the cultures of Penicillium vinaceum AM110.…”

Biohydroxylation of 7‐oxo‐DHEA, a natural metabolite of DHEA, resulting in formation of new metabolites of potential pharmaceutical interest

“…[9] For many years, our team has conducted research on microbial functionalization of compounds of natural origin, including steroid systems. [10][11][12][13][14][15][16][17][18][19][20] Among these transformations, the hydroxylation reactions in an inactivated position of a transformed compound are of particular importance. The use of biotransformation as a tool for modification of the molecules makes it possible to obtain derivatives that are found in the nature in minor amounts, as well as new analogues in amounts which not only allow for determination of their structure, but also for biological assays.…”

“…For many years, our team has conducted research on microbial functionalization of compounds of natural origin, including steroid systems . Among these transformations, the hydroxylation reactions in an inactivated position of a transformed compound are of particular importance.…”