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Synthesis and Biological Evaluation of Sparsomycin Analogues

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Synthesis and Biological Evaluation of Sparsomycin Analogues Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 1981 Synthesis and biological evaluation of sparsomycin analogues Scherer Preston Sanders Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medicinal and Pharmaceutical Chemistry Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/5601 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. SYNTHESIS AND BIOLOGICAL EVALUATION OF SPARSOMYCIN ANALOGUES by Scherer Preston Sanders Duke B.S. , College of William and Mary , 1977 Thesis submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy in the Department of Pharmaceutical Chemistry at the Medical College of Virginia, Virginia Commonwealth University Richmond , Virginia August , 1981 ii This thesis by Scherer Preston Sanders Duke is accepted in its present form as satisfying the thesis requirement for the degree of Doctor of Philosophy . Date : Approved: 1- l I � I · •.•..... ••... •..•.•...•• - TJl ':7 J. � · . •. [v:7. � !� t 9 r ! ..... /) · ....� . �J.) . (q.ft... · ... :r u.l'f . .�l t. I g 8-l........ · .. Cf4r,;2/., . 1'1.f1..... Approved : . Chairman , MCV Graduate Council; Dean , Schoo l of Basic Sciences iii Scherer Preston Sanders Duke 1981 All Rights Reserved iv ACKNOWLEDGMENTS I wish to thank the members of my graduate committee for overseeing this project and especially my advisor , Dr. Marvin R. Boots , for his guidance and encouragement throughout the course of this research and the preparation of this thesis. I also appreciate the helpful advice of Dr . Graham Windridge and his generous gift of the tert-butyloxyazidoformate used in this project . I am grateful to Dr . Al Munson , Dr . Paal Klykken , and Ms . Bernie Kauffmann for their invaluable guidance and assistance with the pharmacological aspects of the project . I gratefully acknowledge the financial support provided by A.H. Robins , Inc. , the A.D. Williams Fund , and the De­ partment of Pharmaceutical Chemistry , MCV/VCU . I thank Mrs . Gayle Hylton for typing the manuscript . A special thanks is extended to my parents , Mr . and Mrs . Carl W. Sanders , and my brother , Carl , for their in­ estimab le encouragement and interest in my career. I especially appreciate the wise advice given me by my father. Lastly , I wish to express my sincere grat i tude to my husband, George , for his patience , encouragement, and under­ standing. It is to him this work is dedicated . v VITA vi TABLE OF CONTENTS COPYRIGHT PAGE --- ---------- ---------- ---- -- - iii VITA ------------ ---------------------------- iv ACKNOWLEDGMENTS - - - ---- ---- ---- -- ------ --- --- v TABLE OF CONTENTS - -- -------------- - --------- vi LIST OF TABLES - - - -------------------- ------- xi LIST OF FIGURES ----------- --------- --------- xii i LIST OF ABBREVIATIONS --- --- -- -- ---- --- - ----- xiv ABSTRACT ---- ------- ---------- ------------- -- xv I. INTRODUCT10N- ----- --- - ------ -- - -- -- - --- - 1 II. RESEARCH AIM --------------------------- 23 III. DISCUSSION OF SYNTHES IS --- --- ---------- 33 IV. DISCUSSION OF PHARMACOLOGICAL RESULTS -- 57 V. CONCLUSIONS --- ------------------------ - 87 VI. EXPERIMENTAL ------------- ------------- - 94 A. General --------------------------- 94 B. Compounds Synthesized ------------- 96 2,4-Dihydroxy- 5-hydroxymethyl-6- methylpyrimidine (�) ---- ------ -- -- 96 (2,4-Dihydroxy- 6-methyl-5-pyrimidinyl ) carboxaldehyde (1)----------------- 96 Carbethoxymethyltriphenylphosphonium Bromide (4a)----------------------- 97 Carbethoxymethylenetriphenylphosphorane (i) ----- - - -- ------------- --------- 97 (E)-Methyl 3- (2,4-Dihydroxy- 6-methyl-5- pyrimidinyl)propenoate (�)--------- 98 vii Page (E)-3-(2,4-Dihydroxy-6-methyl- 5-py­ rImidinyl)propenoic Acid (Q) --------- 99 (E)-(+)-N- (2-Heptanyl )-3- (2,4-dihy­ droxy=6-methyl-5-pyrimidinyl) - 2- propenam ide (19) --------------------- 99 Methyl 2-Amino- 3 -phenylpropanoate Hy­ drochloride (20) --------------- ------ 100 2-Amino-3-phenyl-l-propanol (21) ----- 101 (E)-(+)-N-(1-Hydroxy-3-phenyl-2-propyl)- 3=( 2,4-dIhydroxy-6-methyl- 5-pyrimidinyl)- 2-propenamide (22) ------------------- 101 2-Amino-3-( 4-bromophenyl) propanol (23) 102 (E)- (+)-N-[1-hydroxy-3-(4-bromophenyl)- 2=propyl]-3-(2,4-dihydroxy-6-methyl- 5- pyrimidinyl)-2-propenamide (24) - ----- 103 Diethyl 2-Acetamido- 2- (4-methylben­ zyl)malonate (25) ------------ -------- 104 2-Amino-3- (4-tolyl)propionic Acid (26) 105 4-(2-Amino-3-hydroxypropyl)toluene (27) 106 (E)-(+)-N-[ 1-Hydroxy- 3- (4-methyl­ phenyl)-2-propyl]- 3- (2,4- dihydroxy- 6-methyl- 5-pyrimidiny l)-2-propen- amide (28)--------------------------- 107 4-Methoxybenzyl Bromide (29) -------- 107 Ethyl 2-Acetamido-2-carbethoxy-3-(4- methoxyphenyl)propanoate (30) ------- 108 2-Acetamido-2-carbethoxy-3- (4-methoxy­ phenyl)propanoic Acid (31) ---------- 109 Ethyl 2-Acetamido- 3- (4-methoxyphenyl) propanoate (32) --------------- ------ 109 2-Acetamido-3-(4- methoxyphenyl)pro- panol (33) -------------------- ------ 110 2-Amino-3-( 4-methoxyphenyl ) propanol Hydrochloride (34) ------------------ 111 viii Page (E)- (+)-N-�-Hydroxy-3- (4-methoxy­ phenyl) -2-propyl]-3- (2,4-dihydroxy-6- methyl-5-pyrimidinyl)-2- propenamide (35) - - ------------------ - -- ------- 111 (E)- ( +)-N- (2-Phenylethyl)- 3- (2,4- dlhydroxy- 6-methyl- 5-pyrimidinyl) - 2 -propenamide (36) - --------------- 112 (E)- ( + )-N- [2- (4-Methylphenyl)-ethy l]- 3= ( 2,4- dlhydroxy- 6-methyl- 5-pyrimi­ dinyl)- 2-propenamide (37) --------- 113 (E)- (+)- N- [2- (4-Methoxyphenyl) - ethyl]- 3=( 2,4- dlhydroxy-6-methyl- 5- pyrimi­ dinyl) - 2-propenamide (38) - - ------- 114 (E)- (+)-N- [2- (4- Bromophenyl)-ethyl]- 3=( 2,4- dlhydroxy-6-methyl- 5-pyrimi­ dinyl)-2- propenamide (39)-- ----- --- 114 3- (tert-Butyloxycarbonylamino ) pro­ panoic Acid (40) --------- --- ---- - 115 2,4,5-Trichlorophenyl 3- (tert-Buty­ loxycarbonylamino) propanoate (41) - 116 ( + ) -N- Benzyl- 3- (tert-butyloxycarbo­ nylamino) propanamide (42) ------ --- 116 3- Amino-N-benzylpropanamide Tri­ fluoroacetate (43) ------------ ---- 117 (E)- ( +)-N-Benzyl- 3- [3- (2,4-dihydroxy- 6=methyl=5-pyrimidinyl)- 2-propana­ mido]propanamide (44) - ------ ------ 117 (+)-N- (4-Methylbenzyl)- 3- (tert­ butyloxycarbonylamino) propanamide (45a) ---------------------- ------- 119 ( � )-(�)��_(4 -Methylbenzyl ) - 3- [3- (2,4- dihydroxy-6-methyl- 5-pyrimidinyl) - 2 -propenamido]propanamide (46) ---- 119 (+) -N- (4-Methoxybenzyl)- 3- (tert­ butyloxycarbonylamino) propanamide (47a) - ---------- ----- ------- --- - -- 121 (E)- ( + ) -N- (4-Methoxybenzyl ) - 3- [3- (2, 4=dihydroxy- 6-methyl- 5-pyrimidinyl) - 2- propenamido]propanamide (48) 121 ix Page ( + )-N- ( 4-Bromobenzyl)-3-(tert-butyloxy­ carbonylamino) propanamide (49a) ------- 123 (E�+ )-N- (4-Bromobenzyl)-3-[3-(2,4- dIhydroxy-6-methyl-5-pyrimidinyl- 2-propenamido]propanam ide (50) -------- 124 (+)-N- ( 3,4-Dichlorobenzyl )-3-(tert­ butyloxycarbonylamino )propa'namide (51a) --------------------------------- 125 (E)-( + )-N- (3,4-Dichlorobenzyl)- 3- [3-(2�4-dihydroxy-6-methyl- 5- pyrimidinyl)-2-propenamido]pro- panamide (52) -------------------------- 126 2 � -Phthalyl-DL-aspartic Anhydride (�)-- 127 N4-Benzyl-N2-Phthalyl-DL-aSparagine (54 ) -----=-----------�---------------- 128 N-Benzyloxycarbonyl-DL-aspartic Acid (60) ----------�------------------ 128 N-Benzy loxycarbonyl-DL-aspartic Anhydride (61) -----�------------------ 129 a-Benzyl N-Benzyloxycarbonyl-DL­ aspartate- (62)---------------�--------- 130 8-Benzyl N-Benzyloxycarbonyl-DL­ - -- ---- - ---- - -- aspartate-(62a) -- - - - � - - 131 N- (4-Bromobenzyl)- 3-benzyloxycarbonyl­ amino-2, 5-pyrrolidinedione (62b) ------ 132 2 4 Benzyl � -BenzYloxycarbonyl-� -(4-bromo­ benzyl)-DL-asparaginate (63) ---------- 133 �-(4-Bromobenzyl)- 3-benzyloxycarbo­ nylamino-4-hydroxybutanamide (64)-- -- -- 133 C. Pharmacological Materials and Methods - 135 1. Experimental An imals ------------- 135 2. Preparation of Media ------------- 135 a. Alpha Modificat ion of Eagle 's Minimum Essential Medium ---- 135 b. Complete Dulbecco 's Modified Eagle's Minimum Essential Medium ------------------ ---- 136 x Page c. Spinner 's Medium ----------- 136 3. Enumeriation of Cells 137 4. Tumor Line Maintenance ---------- 137 a. In vivo -------------------- 137 b. In vitro ------------------- 138 5. Preparation of Substrate, Drug , and Inhibitor Solutions --------- 139 a. Control Drugs -------------­ 139 b. Radioisotopes -------------­ 140 c. Analogues of Sparsomycin --- 140 6. Experimental Procedures for the Biological Assays --- ------------ 141 a. DNA Synthes is Inhibition Assay ------------------ - --- 141 (1) Time Course Determination 141 (2) Bone Marrow Cells ------- 142 (3) P388 Cells --- ----------- 142 b. Protein Synthesis Inhibition Assay --------- - -- ----------- 143 (1) Time Course Determina- tion ----------------- - ------ 143 (2) Bone Marrow Cells ---- - - - 143 (3) P388 Cel ls -------------- 144 (4) P815 Cells -------------- 144 c. Cell Growth Studies --------- 145 (1) Time Course Determina- tion ------------------------ 145 (2) ED50 Calculation -------- 145 7. Statistical Analysis ------------ - 145 VII. BIBLIOGRAPHY --------------------- - ------- 14 7 xi LIST OF TABLES TABLE PAGE 14 I. Compet itive Inhibition of N-Acetyl [
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