Alpha-glucosidase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones
AssigneeInternational Center for Chemical Sciences
InventorsAttaur Rahman, Muhammed Iqbal Choudhary, Syed Adnan Ali Shah, Shamsun Nahar Khan
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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.
Claims8
A new chemical compound selected from a group consisting of 6β-Hydroxytibolone (C21H28O3), 15β-Hydroxytibolone (C21H28O3), Δ1,4-Tibolone (C21H26O2), 10β-Hydroxy-Δ4-tibolone (C21H28O3), 11α,15β-Dihydroxytibolone (C21H28O4), 11α,15β-Dihydroxy-Δ5-tibolone (C21H28O4), Δ5-Tibolone (C21H28O2), 6β-Hydroxy-Δ4-tibolone (C21H28O3), 6α-Hydroxy-Δ4-tibolone (C21H28O3), 15α-Hydroxy-Δ4-tibolone (C21H28O3), 6α-Hydroxy-Δ1,4-tibolone (C21H28O3), 6β-Methoxy-Δ4-tibolone (C22H30O3), 3β,6β-Dihydroxytibolone (C21H32O3), 3α-Hydroxy-Δ5-tibolone (C21H32O2), 3α,6β-Dihydroxy-Δ4-tibolone (C21H32O3), 3α,11α-Dihydroxy-Δ4-tibolone (C21H32O3), its derivatives, isomers and salts thereof.
A method of inhibiting alpha-glucosidase enzyme by contacting with Δ4-Tibolone (C21H28O2), 6β-Hydroxytibolone (C21H28O3), Δ1,4-Tibolone (C21H26O2), 6β-Hydroxy-Δ4-tibolone (C21H28O3), 6α-Hydroxy-Δ4-tibolone (C21H28O3), 15α-Hydroxy-Δ4-tibolone (C21H28O3), 6α-Hydroxy-Δ1,4-tibolone (C21H28O3).
A method of producing 6β-Hydroxytibolone, 15β-Hydroxytibolone, and Δ4-Tibolone by contacting tibolone with Rhizopus stolonifer (TSY 0471) under suitable fermentation conditions.
A method of producing Δ1,4-Tibolone, 10β-Hydroxy-Δ4-tibolone, 11α,15β-Dihydroxytibolone, and 11α,15β-Dihydroxy-Δ5-tibolone by contacting tibolone with Cunninghamella elegans (TSY 0865) under suitable fermentation conditions.
A method of producing Δ4-Tibolone by contacting tibolone with Fusarium lini (NRRL 68751) under suitable fermentation conditions.
A method of producing Δ5-Tibolone, 6β-Hydroxy-Δ4-tibolone, 6α-Hydroxy-Δ4-tibolone, 15α-Hydroxy-Δ4-tibolone, 6α-Hydroxy-Δ1,4-tibolone, 6β-Methoxy-Δ4-tibolone, by contacting tibolone with Gibberella fujikuroi (ATCC 10704) under suitable fermentation conditions.
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-Δ5-tibolone, 3α,6β-Dihydroxy-Δ4-tibolone, and 3α,11α-Dihydroxy-Δ4-tibolone by contacting 3α-Hydroxytibolone with Cunninghamella elegans (TSY 0865) under suitable fermentation conditions.
A method for the treatment of diabetes mellitus wherein a therapeutically effective amount of an alpha-glucosidase inhibitor, selected from a group comprising Δ4-Tibolone (C21H28O2), 6β-Hydroxytibolone (C21H28O3), Δ1,4-Tibolone (C21H26O2), 6β-Hydroxy-Δ4-tibolone (C2, H28O3), 6α-Hydroxy-Δ4-tibolone (C21H28O3), 15α-Hydroxy-Δ4-tibolone (C21H28O3), 6α-Hydroxy-Δ4-tibolone (C21H28O3) and their isomers, derivates and salts is chosen for use in humans and animals, optionally with a pharmaceutically acceptable vehicle.
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