I= MICROBIAL TRANSFORMATION OF BIOACTIVE CYCLIC NATURAL PRODUCTS
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Title of Thesis
MICROBIAL TRANSFORMATION OF BIOACTIVE CYCLIC NATURAL PRODUCTS

Author(s)
Syed Ghulam Musharraf
Institute/University/Department Details
University of Karachi
Session
2004
Subject
Chemistry
Number of Pages
284
Keywords (Extracted from title, table of contents and abstract of thesis)
bioactive cyclic natural products, terpenes, steroidal natural products, aspergillus terreus, fermentation protocol

Abstract
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.

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).

Metabolites 63-65 and 68 were found to be new compounds.

[Helv. Chim. Acta, 2004 (accepted)]

(+)-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.

[Helv. Chim. Acta, 2004 (accepted)]

(+)-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.

[He/v. Chim. Acta, 2004, 86, 3450]

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.

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.

[Z. Naturforsch., 2004, 59b, 323]

(+)_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.

[Nat. Prod. Lett., 2003, 16, 345]

(+)-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).

[Nat. Prod Lett., 2003,16,417]

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.

[2. Naturforsch., 2004, 59b, 328]

Modem spectroscopic techniques, including two-dimensional NMR, single X-ray diffraction and mass spectrometry, were employed for the structure elucidation of new metabolites.

Download Full Thesis
5914.05 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
451.09 KB
2 1 Microbial Transformation of Bioactive Cyclic Natural Products 1
3289.97 KB
  1.1 Introduction 1
  1.2 Results and Discussion 28
3 2 Isolation of Compounds from Aspergillus Terreus 132
703.93 KB
  2.1 Introduction 132
  2.2 Results and Discussion 149
4 3 Experiments 169
1193.23 KB
  3.1 General Experimental Conditions 170
  3.2 Pharmacological Activities 171
  3.3 Microorganisms 177
  3.4 Preparation of Media 177
  3.5 General Stage II Fermentation Protocol 180
  3.6 Incubation of the Substrate 181
  3.7 Isolation of Compounds from Aspergillus terreus 227
5 4 Bibliography 231
329.52 KB
6 5 Glossary 251
92.25 KB
7 6 Appendix 257
118.52 KB
8 7 List of Publications 161
52.75 KB