Alpha-glucosidase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones

Abstract

Sixteen new and one known metabolites were obtained by incubation of tibolone and hydroxytibolones with various fungi. Their structures were elucidated by means of a homo and heteronuclear 2D NMR and by HREI-MS techniques. The relative stereochemistry was deduced by 2D NOESY experiment. These metabolites have shown promising inhibitory activities against α-glucosidase enzyme. Seven metabolites exhibited potent inhibitory activity against the α-glucosidase enzyme and were thus found useful in the treatment of diabetes mellitus and other diseases related to the activity of α-glucosidase enzyme.

1 . A new chemical compound selected from a group consisting of 6β-Hydroxytibolone (C 21 H 28 O 3 ), 15β-Hydroxytibolone (C 21 H 28 O 3 ), Δ 1,4 -Tibolone (C 21 H 26 O 2 ), 10β-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 11α,15β-Dihydroxytibolone (C 21 H 28 O 4 ), 11α,15β-Dihydroxy-Δ 5 -tibolone (C 21 H 28 O 4 ), Δ 5 -Tibolone (C 21 H 28 O 2 ), 6β-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 6α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 15α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 6α-Hydroxy-Δ 1,4 -tibolone (C 21 H 28 O 3 ), 6β-Methoxy-Δ 4 -tibolone (C 22 H 30 O 3 ), 3β,6β-Dihydroxytibolone (C 21 H 32 O 3 ), 3α-Hydroxy-Δ 5 -tibolone (C 21 H 32 O 2 ), 3α,6β-Dihydroxy-Δ 4 -tibolone (C 21 H 32 O 3 ), 3α,11α-Dihydroxy-Δ 4 -tibolone (C 21 H 32 O 3 ), its derivatives, isomers and salts thereof. 
   
   
       2 . A method of inhibiting alpha-glucosidase enzyme by contacting with Δ 4 -Tibolone (C 21 H 28 O 2 ), 6β-Hydroxytibolone (C 21 H 28 O 3 ), Δ 1,4 -Tibolone (C 21 H 26 O 2 ), 6β-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 6α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 15α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 6α-Hydroxy-Δ 1,4 -tibolone (C 21 H 28 O 3 ). 
   
   
       3 . A method of producing 6β-Hydroxytibolone, 15β-Hydroxytibolone, and Δ 4 -Tibolone by contacting tibolone with  Rhizopus stolonifer  (TSY 0471) under suitable fermentation conditions. 
   
   
       4 . A method of producing Δ 1,4 -Tibolone, 10β-Hydroxy-Δ 4 -tibolone, 11α,15β-Dihydroxytibolone, and 11α,15β-Dihydroxy-Δ 5 -tibolone by contacting tibolone with  Cunninghamella elegans  (TSY 0865) under suitable fermentation conditions. 
   
   
       5 . A method of producing Δ 4 -Tibolone by contacting tibolone with  Fusarium lini  (NRRL 68751) under suitable fermentation conditions. 
   
   
       6 . A method of producing Δ 5 -Tibolone, 6β-Hydroxy-Δ 4 -tibolone, 6α-Hydroxy-Δ 4 -tibolone, 15α-Hydroxy-Δ 4 -tibolone, 6α-Hydroxy-Δ 1,4 -tibolone, 6β-Methoxy-Δ 4 -tibolone, by contacting tibolone with  Gibberella fujikuroi  (ATCC 10704) under suitable fermentation conditions. 
   
   
       7 . A method of producing 3β,6β-Dihydroxytibolone by contacting 3β-Hydroxytibolone  Cunninghamella elegans  (TSY 0865) under suitable fermentation conditions. A method of producing 3α-Hydroxy-Δ 5 -tibolone, 3α,6β-Dihydroxy-Δ 4 -tibolone, and 3α,11α-Dihydroxy-Δ 4 -tibolone by contacting 3α-Hydroxytibolone with  Cunninghamella elegans  (TSY 0865) under suitable fermentation conditions. 
   
   
       8 . A method for the treatment of diabetes mellitus wherein a therapeutically effective amount of an alpha-glucosidase inhibitor, selected from a group comprising Δ 4 -Tibolone (C 21 H 28 O 2 ), 6β-Hydroxytibolone (C 21 H 28 O 3 ), Δ 1,4 -Tibolone (C 21 H 26 O 2 ), 6β-Hydroxy-Δ 4 -tibolone (C 2 , H 28 O 3 ), 6α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 15α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ), 6α-Hydroxy-Δ 4 -tibolone (C 21 H 28 O 3 ) and their isomers, derivates and salts is chosen for use in humans and animals, optionally with a pharmaceutically acceptable vehicle.