I= ISOLATION AND CHARACTERIZATION OF SECONDARY METABOLITES FROM MARINE FUNGI OF ARABIAN SEA AND MECROBIAL TRANSFORMATION OF SOME BIOACTIVE COMPOUNDS
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Title of Thesis
ISOLATION AND CHARACTERIZATION OF SECONDARY METABOLITES FROM MARINE FUNGI OF ARABIAN SEA AND MECROBIAL TRANSFORMATION OF SOME BIOACTIVE COMPOUNDS

Author(s)
Syed Adnan Ali Shah
Institute/University/Department Details
University of Karachi, Pakistan
Session
2005
Subject
Chemistry
Number of Pages
317
Keywords (Extracted from title, table of contents and abstract of thesis)
secondary metabolites, marine fungi, arabian sea, aioactive compounds, tibolone, cortexolone, pregnenolone, e-guggulsterone

Abstract
This Ph.D. dissertation comprises of three parts. Part A describes the microbial transformations studies on nine bioactive compounds. Part B comprises on isolation and characterization of some secondary metabolites from marine fungi of Arabian Sea, while the Part C describes the results of various biological screenings on compounds isolated or obtained by biotransformation.

Part A The microbial transformation of nine bioactive steroidal compounds was performed. This includes transformation of tibolone (51), 3B-hydroxytibolone (65), 3a-hydroxytibolone (66), E- guggulsterone (71), dehydroepiandrosterone (82), cortexolone (90), pregnenolone acetate (101),ethylestrenol (107), and nandrolone (110). These compounds were subjected to biotransformation using the whole cell fermentation techniques and a total of 54 metabolites were obtained. Twenty five metabolites were found to be new on the basis of detailed spectral analyses. Incubation of tibolone (51) with plant pathogen Rhizopus stolonifer, Fusarium lini, Cunninghamella elegans and Gibberilla fujikuroi was carried out, leading to the identification of twelve new and one known metabolites 52-64. They were identified as 6p-hydroxytibolone (52), 15p-hydroxytibolone (53), ˆ†4- -tibolone (54), ˆ†4-tibolone (55),10B-hydroxy-.ˆ†4 tibolone (56), 11a,15B-dihydroxytibolone (57), lla,15B-dihydroxy-ˆ†5-tibolone (58), ˆ†5- tibolone (59), 6B- hydroxy-ˆ†4 -tibolone (60), 6a-hydroxy-ˆ†4-tibolone (61), 15a-hydroxy-ˆ†4-tibolone (62), 6a- hydroxy-ˆ†1,4-tibolone (63), and 6p-methoxy-ˆ†4-tibolone (64).

[Tetrahedron, 2005 (Accepted)] Incubation of 3B-hydroxytibolone (65) with Cunninghamella elegans led to the formation of a new metabolite 67, which was identified as 3B,6B-dihydroxytibolone. Fermentation of 3a-hydroxytibolone (66) with Cunninghamella elegans led to formation of three new polar metabolites 68-70. They were identified as 3a-hydroxy-ˆ†5-tibolone (68), 3a,6B-dihydroxy-l14-tibolone (69), and 3a, 11 a-dihydroxy-ˆ†4-tibolone (70).

[Tetrahedron, 2005 (Accepted)]bFungal transformation of E-guggulsterone (71) with Rhizophus stolonifer, Fusarium lini, Cunninghamella elegans and Gibberella fujikuroi yielded two previously known mono hydroxylated metabolites 72 and 73, and eight new mono-, di- and tri-hydroxylated metabolites 74-81. These were identified as 11a-hydroxy-E-guggulsterone((11a,17E)-11-hydroxypregna-4,17-diene-3,16-dione) (72), 11a-hydroxy-Z-guggulsterone((lla,17Z)-11-hydroxypregna-4,17-diene-3,16-dione)(73),17,20-dihydro12hydroxyguggulsterone((12a)-12-hydroxypregn-4- ene-3,16-dione)(74),17,20-dihydro-6p, 11 a-dihydroxyguggulsterone 6B,11a)6,11dihydroxypreene3,16dione)(75),6B,11adihydroxyZguggulsteron((6B,11a,17Z)-6,11-dihydroxypregna-4,17-diene-3,16 dione) (76), 6B 11 a-dihydroxy-E-guggulsterone((6B, 11a,17E)-6, 11-dihydroxypregna-4, 17-diene-3,16-dione) (77), (11 a, 16B)-11,16- dihydroxypregn-4-en- 3-one (78), 17,20-dihydro-7B, 11 a, 12a-trihydroxyguggulsterone ((7B,lla,12a)-7,11,12 trihydroxypregn-4-ene-3,16-dione) (79), 1B,11a,12B-trihydroxy-Z-guggulsterone((1B,11a,12B,17Z)-I,11,1 trihydroxypregna4,17-diene-3,16-dione) (80), and 1B, 11 a, 12B-trihydroxy-E-guggulsterone((1B, 11 a, 12B, 17 E)-1,11, 12-trihydroxypregna-4, 170- diene-3,16-dione) (81).

[Chern. Biodiv., 2005,2,516-524] Transformation of dehydroepiandrosterone (DHEA) (82) with a plant pathogen Rhizopus stolonifer, resulted in the production of seven metabolites, identified as 3B,17B-dihydroxyandrost-5-ene (83), 3p,17P-dihydroxyandrost-4-ene (84), 17P-hydroxyandrost-4-en-3- one (85), 3B,11B-dihydroxyandrost-4-en-17-one (86), 3B,7a-dihydroandrost-5-en-17-one (87), 3B, 7a, 17B-trihydroxyandrost-5-ene (88), and 11 B-hydroxyandrost-4,6-diene-3, 17 -dione (89).

[Nat. Prod. Res., 2003,17,215] Structural transformation of cortexolone (90) was carried out by fungi, Rhizopus stolonifer, Fusarium lini and Cunninghamella elegans using solid phase fermentation. This resulted in the formation of ten polar metabolites including 17a,21-dihydroxypregnI,4-diene- 3,20-dione (91), 16B, 17a,21-trihydroxypregn-1 ,4-diene-3,20-dione (92), 17 a,21- dihydroxypregn-I ,4-diene-3, 11 ,20-trione (93), 15B, 17a,21-trihydroxypregn-4-ene-3,20-dione (94), androsta-I ,4-diene-3, 17 -dione (95), 17B-hydroxyandrosta-l ,4-dien-3-one (96), 16B, 17B- dihydroxyandrosta-I,4-dien-3-one (97), 11 a, 17B-dihydroxyandrosta-l ,4-dien-3-one (98), 16B- hydroxyandrosta-l ,4-diene-3, 17 -dione (99), and 15B-hydroxyandrosta-l ,4-dien-3-one (100). These metabolites have exhibited varying degree of inhibitory activities against the prolyl endopeptidase (pep) enzyme.

[Nat. Prod. Res., 2005 (Submitted)] Fermentations of pregnenolone acetate (101) with Cunninghamella elegans and Rhizopusstolonifer, have yielded six oxidative metabolites identified as androsta-l,4-diene-3, 17 €“dione (95), 3B-hydroxypreg-6-en 20-one (102), 6B,15B-dihydroxyandrost-4-ene-3,17-dione (103),11a,15B-dihydroxypreg-4-ene-3,20-dione(104),11a-hydroxypreg-4-ene-3,20-dione (105), and 6B, 15B-dihydroxypreg-4-ene-3,20-dione (106).

[Chem Pharm. Bull., 2005 (Accepted)] Microbial transformation of ethylestrenol (107) was carried out with Rhizopus stolonifer (TSY 0471), which yielded two oxidative metabolites named as 17a-ethyl-3B,17B-dihydroxy-19- nomdrost-4-ene (108), and 17a-ethyl-17B-hydroxy-19-norandrost-4-en-3-one (109).

Incubation of nandrolone (11 0) with Rhizopus stolonifer yielded a known metabolite 19- norandrost-4-ene-3, 17 -dione (111), and a new metabolite, 6a, 17B-dihydroxy-19-norandrost-l,4- dien-3-one (112).

Part B The part B of the thesis presents detail of an isolation study on secondary metabolites of a marine fungus Aspergillus fumigatus. This resulted in the isolation of three known metabolites, kojic acid (131), 3,4-dihydroxy-2,5-toluquinone (132), and 3,6-dihydroxy-p-toluquinone (133). This is the first report of the isolation of kojic acid from this species.

Part C Part C of the thesis comprises on results of various biological screenings on compounds. Metabolites 52, 55 and 56 exhibited potent inhibitory activity against the glucosidase enzyme. All transformed analogues of tibolone (51) exhibited mild to potent inhibition against the enzyme tyrosinase, except compounds 55, 59, 61 and 62. Compound 57 was founded to be the most potent inhibitor of tyrosinase enzyme in this series. Metabolite 73 has exhibited an scavenging activity against the DPPH radicals (69.1 %) in a non-physiological assay. Hydroxylated metabolites of E-guggulsterone (71) have exhibited antibacterial activity against Escherichia coli, Bacillus subtilis. Shigella jlexenari, Staphylococcus aureus. Pseudomonas aeruginosa and Salmonella typhi strains. Compounds 103 and 106 showed a pronounced inhibitory activity against the enzymes acetylcholinesterase (AChE; EC 3.1.1. 7) and butyry1cholinesterase (BChE; E.C 3.1.1.8). The cortexolone (90) and its metabolites exhibited pronounced inhibitory activity against the enzyme prolyl endopeptidase (PEP).

Download Full Thesis
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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
1195.86 KB
2 1 Microbial Transformation of some Bioactive Compounds 1
13649.7 KB
  1.1 Introduction 2
  1.2 Results and Discussion 35
  1.3 Experimental 145
3 2 Isolation and Characterization of Secondary Metabolites From Marine Fungi 225
1067.44 KB
  2.1 Introduction 226
  2.2 Results and Discussion 237
  2.3 Experimental 243
4 3 Biological 249
1189.78 KB
  3.1 a-Glucosidase Inhibitory Activities of Tibolone and its Metabolites 250
  3.2 Tryrosinase Inhibitory Activities of Tibolone and its Metabolites 254
  3.3 Prolyl endopeptidase Inhibitory Activities of Cortexolone and its Metabolites 258
  3.4 Cholinesterae Inhibitory Activities of Pregnenolone Acetate and its Metabolites 262
  3.5 Antioxidant Activities of E- Guggulsterone and its Metabolites 265
  3.6 Antibacterial Activities of E- Guggulsterone and its Metabolites 269
5 4 References 273
1004.22 KB
6 5 Glossary 290
216.33 KB
7 6 List of Publications 295
44.28 KB