MICROBIAL TRANSFORMATION OF BIOACTIVE CYCLIC NATURAL PRODUCTS

This Ph.D. dissertation describes the microbial transformation of eight biologically active terpenes and steroidal natural products: (-)-ambrox (56), (+)-sclareolide (61), (+)isolongifolen-4-one (77), (-)-isolongifolol (78), norethisterone (96), 17a-ethynylestradiol (97), (+)-androsta-l,4-dien-3,17-dione (103) and (+)-adrenosterone (110). These compounds were subjected to fungal transformations using a standard two-stage fermentation technique, leading to the isolation of 38 metabolites, of which 16 were new.\ud \ud Incubation of (-)-ambrox (55) with a number of fungi afforded, 3-oxoambrox (60), sclareolide (61), 3B-hydroxyambrox (62), la-hydroxyambrox (63), la,lladihydroxyambrox (64), la,6a-dihydroxyambrox (65), 3B,6B-dihydroxyambrox (66), tetra-nor-8,12-dihydroxylabdane(67)andla,6a,lla-trihydroxyambrox(68).\ud \ud Metabolites 63-65 and 68 were found to be new compounds.\ud \ud [Helv. Chim. Acta, 2004 (accepted)]\ud \ud (+)-Sclareolide (61) yielded 3-oxosclareolide (69), 3J3-hydroxysclareolide (70), 2a.hydroxysclareolide (71), 2a.,3B -dihydroxysclareolide (72), 1a.,3 B-dihydroxysclareolide (73), and 3B-hydroxyepisclareolide (74)on incubation with Cunninghamella elegans. Compounds 71, 72 and 74 were found to be new. The transformed metabolites of sc1areolide i.e. 69-74, showed significant phytotoxicity compared to the parent compound.\ud \ud [Helv. Chim. Acta, 2004 (accepted)]\ud \ud (+)-Isolongifolen-4-one (77) on fermentation with various fungal strains afforded mainly the new hydroxylated metabolites: (7R)-12-hydroxyisolongifolen-4-one (79), (7S}-12hydroxyisolongifolen-4-one (80), (11S}-9-hydroxyisolongifolen-4-one (81), (9S}-9hydroxyisolongifolen-4-one (82) and (l0R)-9-hydroxyisolongifolen-4-one (83). The metabolites and their chemical derivatives showed potent tyrosinase inhibitory activity.\ud \ud [He/v. Chim. Acta, 2004, 86, 3450]\ud \ud The microbial transformation of (- )-isolongifolol (78) yielded three new metabolites: 10oxoisolongifolol (93), 10a.-hydroxyisolongifolol (94) and 9a.-hydroxyisolongifolol (95). Compound 94 showed potent activity in butyrylcholinesterase assay.\ud \ud Incubation of norethisterone (96) with Cephalosporium aphidicola afforded an oxidized metabolite 17a-ethynylestradiol (97). Further incubation of compound 97 yielded six oxidative metabolites: 19-nor-17a-pregna-I,3,5 (I0)-trien-20-yne-3,4, 17 B.triol (98), 19nor-17a-pregna-I,3,5 (l0)-trien-20-yne-3,7 a,17 P.triol (99), 19-nor-17a-pregna-I,3,5 (1 0)-trien-20-yne-3, II a, 17 B.triol (100), I 9-nor-17a-pregna-l ,3,5 (10)-trien-20-yne 3,6p,I 7B.triol (101) and 19-nor-17a-pregna-I,3,5 (l0)-trien-20-yne-3,17 B.diol-6P. methoxy (102). Compound 102 was found to be a new one.\ud \ud [Z. Naturforsch., 2004, 59b, 323]\ud \ud (+)_Androsta-1,4-dien-3,17-dione (103) was converted into six biotransformed products: androst-4-en-3,17-dione (104), 17B_hydroxyandrosta-l,4-dien-3-one (105), 11 ahydroxyandrosta-l,4-dien-3,17-dione (106), 11a-hydroxyandrost-4-en-3,17-dione (107), 17p,11a-dihydroxyandrost-4-en-3-one (108) and 17B,11a-dihydroxyandrosta-l,4-dien-3one (109.\ud \ud [Nat. Prod. Lett., 2003, 16, 345]\ud \ud (+)-Adrenosterone (110) yielded three transformed products: 17(3-hydroxyandrost-4-en3,11,17-trione (111), androsta-1,4-dien-3,11,17-trione (112) and 17(3-hydroxyandrosta1,4-dien-3,11-dione (113).\ud \ud [Nat. Prod Lett., 2003,16,417]\ud \ud In addition, chemical investigation on a marine fungus Aspergillus terreus led to the isolation of a new 131 and five known 132-136 metabolites. Compounds 132 and 133 were also isolated as a new source. All metabolites were tested for antifungal and antioxidant activities.\ud \ud [2. Naturforsch., 2004, 59b, 328]\ud \ud Modem spectroscopic techniques, including two-dimensional NMR, single X-ray diffraction and mass spectrometry, were employed for the structure elucidation of new metabolites