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31295013018931.Pdf (6.180Mb) SYNTHESIS OF STEROL BIOSYNTHESIS INHIBITORS AND METABOLISM OF ISOTOPICALLY LABELED STEROLS BY Saccharomyces cerevisiae by WEN ZHOU, B.S., M.S. A DISSERTATION IN CHEMISTRY Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Approved May, 1998 ACKNOWLEDGMENTS I would like to express my deepest thanks to my advisor, Dr. W. David Nes, for his expert support and helpful advice during my graduate education at Texas Tech University. I would also like to thank Dr. Edward J. Parish and Dr. George I. Makhatadze for serving on my doctoral committee. I am grateful to former and current postdoctoral associates and graduate students in Dr. Nes' laboratory for their kind help, including: Dr. Dean Guo, Dr. Yusen Tong, Dr. Zhonghua Jia, Monica Lopez, Brian S. McCourt, Wenxu Zhou, Anil T. Mangla, Derek S. Nichols, Ling He. I would also like to thank Dr. John N. Marx for his technical advice and help for this research. I am also in debt to Mr. David Purkiss for his assistance in performing NMR spectral work for this research. Finally, I would like to thank my parents, Lijun Wang and Bingxian Zhou for their constant support and encouragement. The support of the Welch Foundation is greatly appreciated. 11 CONTENTS ACKNOWLEDGMENTS 11 ABSTRACT ix LIST OF TABLES xi LIST OF FIGURES xii LIST OF SCHEMES xiv CHAPTER 1. INTRODUCTION 1 1.1. Structure and nomenclature 1 1.2. Background of sterol biosynthesis 2 1.3. Isopentenoid biosynthesis 4 1.4. §qualene biosynthesis 5 1.5. Lanosterol and cycloartenol biosynthesis 6 1.6. Pathways of sterol biosynthesis in fungi, animals, and plants 7 1.7. Sterol methylation mechanism 10 1.8. X*-group mechanism 12 1.9. Structure-fiinction relationships 13 1.10. Sterol methylation inhibitors 15 2. STUDIES ON STEROL METHYLATION MECHANISM 24 2.1. Mechanism studies of the sterol methylation in yeast 24 2.2. Mechanism studies of phytosterol methylation 28 2.3. Mechanismstudiesof the second sterol methylation 29 2.4. Molecular modeling and analysis of C-20 configuration 32 3. STUDIES ON STEROL METHYLATION INHIBITORS 37 3.1. Design, preparation and inhibition studies of C-20, C-21 and C-22 related sterol inhibitor 37 3.2. Design, preparation and inhibition studies of C-23 related inhibitors 42 111 3.3. Design, preparation and inhibition studies of C-24 related inhibitor 43 3.4. Design, preparation and inhibition studies of C-25 related inhibitors 44 3.5. Design, preparation and inhibition studies of C-26 and C-27 related inhibitors 45 3.6. Design, preparation and inhibition studies of C-28 related inhibitors 50 3.7. Summary 54 MATERLALS AND METHODS 60 4.1. Chemical reagents 60 4.2. Methods 60 NATURAL PRODUCTS ISOLATION AND BIOORGANIC SYNTHESIS 62 5.1. Isolation of cycloartenol from y-oryzanol (Figure 5.1) 62 5.2. Protection of 3 P hydroxyl group of sterols (Figure 5.2) 64 5.2.1 Acetate ester 66 5.2.1.1. Formation of acetate ester 66 5.2.1.2. Cleavage of acetate ester 66 5.2.2. (3a, 5)-Cyclo-6p-methoxy ether 66 5.2.2.1. Formation of (3a, 5)-cyclo-6p-methoxy ether 66 5.2.2.2. Cleavage of (3a, 5)-cyclo-6p-methoxy ether 68 5.2.3. Tetrahydropyranyl ether 69 5.2.3.1. Formation of tetrahydropyranyl ether 69 5.2.3.2. Cleavage of tetrahydropyranyl ether 69 5.2.4. Summary 70 13 5.3. Preparation of [27- C]lanosterol (Scheme 2.1) and [27-^^C]zymosterol 70 5.3.1 2-[^^C]Methyl-1 -acetoxy-methyl triphenylphosphonium iodide 44 70 IV 5.3.2. 24-al Lanosterol 46 71 5.3.3. 3p-Acetoxy-26-ester-[27-^^C]lanosterol47 71 5.3.4. 3p-Acetoxy-26-ol-[27-^^C]lanosterol48 72 5.3.5. [27-'^C]Lanosterol 49 72 5.3.6. [27-^^C]Zymosterol 73 5.4. Biosynthesis of [27-^^C]ergosterol 50 in S. cerevisiae strain GL7 (Scheme 2.2.1) 74 5.5. Preparation of [24-^H]lanosterol 53 and biosynthesis of [25-^H]ergosterol 54 in S. cerevisiae strain GL7 (Scheme 2.2) 75 5.5.1. 3p-Acetoxy-24-keto lanosterol 51 75 5.5.2. [245-^H]-245-ol-3p-Acetoxy lanosterol 52 75 5.5.3. [24-^H]Lanosterol 53 76 5.5.4. Biosynthesis of [25-^H]ergosterol 54 76 5.6. Biosynthesis of [28-^H2]ergosterol 56 in S. cerevisiae strain GL7 (Scheme 2.3) 76 5.7. Preparation of 20i?-22-aza-cholest-5-en-3P-ol 58a and 205'-22-aza-cholest-5-en-3P-ol 58b (Scheme 3.1) 76 5.8. Preparation of 3P-ol-cholesta-5(6), 20(22)£, 24(25)- trien-20-one 61, 3p-ol-cholesta-5(6), 20(21), 24(25)- trien-20-one 62 and 3p-ol-cholesta-5(6), 17(20)Z, 24(25) -trien-20-one 63 (Scheme 3.2) 78 5.8.1. 3p-Tetrahydropyranylooxy-21 -nor-cholesta- 5, 24-dien-20-one 59 78 5.8.2. 3 p-Tetrahydropyranylooxy-cholesta- 5(6), 20(21), 24(25)-trien-20-one 60 79 5.8.3. 3p-ol-Cholesta-5(6), 20(22)^, 24(25)-trien-20-one 61, 3p-ol-cholesta-5(6), 20(21), 24(6)-trien-20-one 62 and 3p-ol-cholesta-5(6), 17 (20)Z, 24(25)-trien-20-one 63 79 5.9. Preparation of 20-epidesmosterol 72b (Scheme 3.3) 81 5.9.1. i-Pregnenolone 64 81 5.9.2. 20-Keto-24(25)-en-i-sterol 65 81 5.9.3. 20(21), 24(25)-dien-i-Sterol 66 82 5.9.4. 20(21)-en-24(25)-Epoxide-i-sterol67 82 5.9.5. 20(R, 5)-24(25)-Epoxide-i-sterol 68 83 5.9.6. 20(i?, 5)-25-ol-i-Sterol 69 83 5.9.7. 20iR, S)-24(25)-en- i-Sterol 70 and 20(R, S)- 25(27)-en- i-sterol 71 83 5.9.8. Desmosterol 72a and 20-epidesmosterol 72b 84 5.10. Preparation of 23-aza-cholest-5-en-3p-ol 76 and 25-aza-cholesta-5, 22-dien-3p-ol 77 (Scheme 3.4) 86 5.10.1. (3a, 5)-Cyclo-6p-methoxy-cholest-22-al 75 S6 5.10.2. 23-Aza-cholest-5-en-3-ol 76 86 5.10.3. 25-Aza-cholesta-5, 22-dien-3-ol 77 87 5.11. Preparation of 24-aza-cholest-8-en-3p-ol 82 (Scheme 3.5) 88 5.11.1. 3p-Acetoxy-cholest-8-en-24-al 79 88 5.11.2. 3p-Acetoxy-24-[(tert-butyldimethylsilyl)oxy] -cholesta-8(9), 23(24)-dien 80 88 5.11.3.3p-Acetoxy-cholest-8-en-23-al81 89 5.11.4. 24-Aza-cholest-8-en-3p-ol 82 89 5.12. Preparation of 25-aza sterols. (Scheme 3.6) 90 5.12.1. 25-Aza sterols 90 5.12.2. 26-Nor-25-aza-cholest-8-en-3P-ol 85 90 5.13. Preparation of 26, 27-dinor-cholesta-8(9), 24(25) -dien-3p-ol 86 (Scheme 3.6) 92 5.14. Preparation of 26, 27-cyclopropylidene sterols (Scheme 3.7) 92 3 5.14.1. Preparation of [3a- H]-26, 27-cyclopropylidene -cholesta-8, 24-dien-3P-ol 92a 92 5.14.1.1. 26, 27-Cyclopropylidene-cholesta-8, 24- dien-3P-ol90 92 5.14.1.2. 3-Keto-26, 27-cyclopropylidene- cholesta-8(9), 24(25)-dien-3p-ol 91 93 VI 5.14.1.3. [3a-^H]-26, 27-Cyclopropylidene- cholesta-8, 24-dien-3p-ol 92 94 5.14.2. Preparation of 26, 27-cyclopropylidene-9p, 19- cyclopropyl-cholesta-24-en-3p-ol 93 94 5.14.3. Preparation of 26, 27-cyclopropylidene-4,4-dimethyl- 14a-methyl-cholesta-8(9), 24(25)-dien-3p-ol 94 95 5.14.4. Preparation of 26, 27-cyclopropylidene-cholesta- 5(6), 24(25)-dien-3p-ol 95 95 5.15. Preparation of 24(25), 26(26')-diene sterols (Scheme 3.8) 95 5.15.1.3 p-Acetoxy-26-al zymosterol 96 96 5.15.2. 24(25)-26(26')-Diene zymosterol 97 96 5.15.3. 24(25)-26(26')-Diene cycloartenol 98 97 5.15.4. 24(25)-26(26')-Diene lanosterol 99 97 5.15.5. 24(25)-26(26')-Diene desmosterol 100 97 5.16. Preparation of 8(9), 14(15), 24(25)-trien-25-ethylnyl- cholesta-3P-ol 103 (Scheme 3.9) 97 5.17. Preparation of 24(R, S), 25-methano sterols (Scheme 3.10) 100 5.17.1. 3p-Acetoxy-24, 25-dichloromethano zymosterol 104 100 5.17.2. 24 (R, S), 25-Methano-zymosterol 105 100 5.17.3. 24 (R, S), 25-Methano-cycloartenol 106 101 5.17.4. 24 (R, S), 25-Methano-lanosterol 107 101 5.17.5. 24 {R. 5), 25-Methano-desmosterol 108 102 5.18. Preparation of 24(.^, 5), 25-epimino lanosterol 110, 25-amino lanosterol 111 and 28-A^-methyl-24(i^, S), 25-epimino lanosterol 112 (Scheme 3.11) 102 5.18.1. Preparation of 24 (R, S), 25-epimino lanosterol 110 102 5.18.2. Preparation of 25-amino lanosterol 111 103 5.18.3. 28-A^-Methyl-24(i?, S), 25-epimino lanosterol 112 103 5.18.4. 24(R, S), 25-Epimino zymosterol 113 104 5.19. 24, 28-Methano cholesterol US (Scheme 3.12) 104 Vll 5.20. 24(R, S), 28(i?, 5)-Methano fucosterol 117 (Scheme 3.12) 104 5.21.
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