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Synthesis of Novel Nitric Oxide Donors and Prodrugs of 5- Fluorouracil

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Synthesis of Novel Nitric Oxide Donors and Prodrugs of 5- Fluorouracil SYNTHESIS OF NOVEL NITRIC OXIDE DONORS AND PRODRUGS OF 5- FLUOROURACIL DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Tingwei Cai, M.S. ***** The Ohio State University 2005 Dissertation Committee: Approved by Professor Peng George Wang, Advisor Professor Robert S. Coleman _________________________________ Professor Matthew S. Platz Advisor Graduate Program in Chemistry ABSTRACT This dissertation describes my Ph.D. work that focused on the synthesis and evaluation of novel nitric oxide donors, and the synthesis of derivatives of 5-fluorouracil. In chapter 1, a series of alkyl and aryl N-hydroxyguanidines were synthesized and demonstrated to act as substrates of nitric oxide synthases (NOS). The discovery of these non-amino acid hydroxyguanidines as novel substrates also led to the discovery of a novel-binding mode of NOS. In chapter 2, in order to achieve site specific delivery of nitric oxide (NO), a new class of glycosidase activated NO donors has been developed. Glucose and galactose were covalently coupled to 3-morphorlinosydnonimine (SIN-1), a mesoionic heterocyclic NO donor, via a carbamate linkage at the anomeric position. The β-glycosides were successfully prepared for these conjugates, while the α glycosidic compounds were very unstable. The new stable sugar-NO conjugates could release NO in the presence of glycosidases. Such NO prodrugs may be used as enzyme activated NO donors in biomedical research. In chapter 3, a new sialated diazeniumdiolate has been synthesized and the glycosylation product was exclusively an α anomer. This new nitric oxide donor exhibited significantly improved stability as compared to its parent diazeniumdiolate salts and it ii could be efficiently hydrolyzed by neuraminidase to release nitric oxide with a Km of 0.14 mM. The sialic acid-NO conjugate would be a valuable prodrug that targets NO to influenza viruses. In chapter 4, two classes of prodrugs of 5-fluorouracil (FU) were synthesized. The first type is FU-NO conjugate. The synthesized compounds showed greater cytotoxicities than 5-fluorouracil for DU 145 human prostate and HeLa cancer cells. The second type is carbohydrate-FU conjugate. A new reverse glycosadition was also developed to prepare sugar conjugates. In chapter 5, 7-carboxylindazole, as well as 5- and 6-carboxylindazoles was synthesized. These compounds were designed as isosteres of 7-nitroindazole, a well-known inhibitor of NOS. However, they did not show potent inhibition to NOS. iii This dissertation is dedicated to my wife, Zhenling, whose love, understanding, devotion and support will never be forgotten. iv ACKNOWLEDGMENTS I would like to express my sincere gratitude to my advisor, Professor Peng George Wang, for his support, scientific guidance and allowing me the freedom to explore the wonderful world of chemistry in his lab during the past five years. I would like to thank my Ph.D. committee: Professor Robert S. Coleman and Professor Matthew Platz for their invaluable advice and time. I am indebted to the following professors for their inspiring courses: Dr. Robert S. Coleman, Dr. Martin Newcomb, Dr. Maarten Postema, Dr. John Montgomery, Dr. Mark Spaller, Dr. Ashok Bhagwat, Dr. David Benson, Dr. David Rorabacher. I am thankful to all my colleagues and members of the Wang’s research group. I would especially like to thank Dr. Xiaoping Tang, Dr. Peter Andreana, Dr. Adam Janczuk, Dr. Ming Xian, Dr. Lizhi Zhu, Dr. Guisheng Zhang, Mr. Yun Zhang, Mr. Yalong Zhang, Ms. Dongning Lu, Ms. Megan Landerholm, Mr. Xuejun Wu and other people helped me in the research. I also thank Dr. Duxin Sun, Dr. Paul Braunschweiger and Dr. Richard Silverman for their assistance in biological assay. v I would like to thank Dr. David Hart, Mrs. Judith Brown, Ms. Jennifer Bates and all the administrative staff for their very friendly and resourceful assistance. Finally, I would like to thank my beloved parents and brothers. My whole Ph.D. work would not have been possible if not for the love, appreciation, patience and consideration from my wife Zhenling. vi VITA November, 1969. Born – Jilin, China July, 1992. Bachelor of Science Beijing Medical University July, 1995. Master of Science Beijing Medical University 2000 – 2003. Teaching Asst. Wayne State University. 2003 – 2004. Teaching Asst. The Ohio State University. 2004 – 2005. Research Asst. The Ohio State University. PUBLICATIONS Research Publications 15. Cai, T. B.; Lu, D.; Tang, X.; Zhang, Y.; Landerholm, M.; Wang, P. G. “New glycosidase activated nitric oxide donors: glycose and 3-morphorlinosydnonimine conjugates”, J. Org. Chem. 2005, 70, 3518-3524. 14. Cai, T. B.; Lu, D.; Wang, P. G. “N-Hydroxyguanidines as substrates of nitric oxide synthases”, Curr. Topics Med. Chem. 2005, in press. 13. Cheng, H; Cao, X.; Xian, M.; Fang, L.; Cai, T. B.; Ji, J. J.; Tunac, J. B.; Sun, D; Wang, P. G. “Synthesis and enzyme-specific activation of carbohydrate- geldanamycin conjugates with potent anticancer activity”, J. Med. Chem. 2005, 48, 645 -652. 12. Cai, T. B.; Lu, D.; Landerholm, M.; Wang, P. G. “ Sialated diazeniumdiolate: a new sialidase-activated nitric oxide donor”, Org. Let. 2004, 6, 4203-4205. vii 11. Wang, P. G.; Cai, T. B.; Taniguchi, N. (book eds) “Nitric oxide donors: for pharmaceutical and biological applications” 2005, Wily-VCH, Weinheim, Germany. 10. Cai, .T. B.; Wang, P. G. “Recent development of anticancer NO donors” Exp. Opin. Ther. Patents 2004, 14, 849-857. 9. Cai, T. B.; Tang, X.; Nagorski, J.; Brauschweiger, P. G.; Wang, P. G. “Synthesis and cytotoxicity of 5-fluorouracil/diazeniumdiolate conjugates” Bioorg. Med. Chem. 2003, 11, 4971-4975. 8. Jia, Q.; Cai, T.; Huang, M.; Li, H.-Y.; Xian, M.; Poulos, T. L.; Wang, P. G. “Isoform-selective Substrates of nitric oxide synthase” J. Med. Chem. 2003, 46, 2271-2274. 7. Tang, X. ; Cai, T.; Wang, P. G. “Synthesis of beta-lactamase activated nitric oxide donors” Bioorg. Med. Chem. Lett. 2003, 13, 1687-1690. 6. Li, H.-Y.; Shimizu, H.; Flinspach, M.; Jamal, J.; Yang, W.-P.; Xian, M.; Cai, T.; Wen, E. Z.; Jia, Q.; Wang, P. G.; Poulos, T. L. “Novel binding mode of N-alkyl- N'-hydroxyguanidine to neuronal nitric oxide synthase reveals insights into NO biosynthesis” Biochemistry, 2002, 41, 13868-13875. 5. Xian, M.; Fujiwara, N.; Wen, Z.; Cai, T.; Kazuma, S.; Janczuk, A. J.; Tang, X.; Telyatnikov, V. V.; Zhang, Y.; Chen, X.; Miyamoto, Y.; Taniguchi, N.; Wang, P. G. “Novel substrates for nitric oxide synthases” Bioorg. Med. Chem. 2002, 10, 3049-3055. 4. Cai, T.; Xian, M.; Wang, P. G. “Electrochemical and peroxidase oxidation study of N'-Hydroxyguanidine derivatives as NO donors” Bioorg. Med. Chem. Lett. 2002, 12, 1507-1510. 3. Jia, Q.; Janczuk, A.; Cai, T.; Xian, M.; Wen, Z.; Wang, P. G. “Nitric oxide donors as anti-cancer agents” Exp. Opin. Ther. Patents 2002, 12, 819-826. 2. Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, A. J. "Nitric oxide donors: chemical activities and biological applications" Chem. Rev. 2002, 102, 1091-1134. 1. Cai, T.; Min, J.; Zhang, L. “Synthesis of lactosyl phosphate diester derivatives of nucleosides” Carbohydr. Res. 1997, 303, 113-117. viii FIELDS OF STUDY Major Field: Chemistry ix TABLE OF CONTENTS P a g e Abstract. ii Dedication. .iv Acknowledgments . .v Vita . .vii List of Schemes. .. xii List of Tables. xiv List of Figures . .xv List of Abbreviations . .xvii Chapter: 1 N-Hydroxyguanidines as novel nitric oxide donors . .1 1.1 Introduction . .. .1 1.2 Synthesis and NO releasing ability of N-hydroxyguanidines as NOS substrates. .5 1.3 Discovery of a novel binding mode for NOS. .. .11 1.4 Electrochemical and peroxidase oxidation studies of N-hydroxyguanidines. .16 1.5 Conclusion. .23 1.6 Experimental. .24 2 New carbohydrate and 3-morphorlinosyndnonime conjugates. .33 2.1 Introduction. .33 2.2 Synthesis of sugar-SIN1 conjugates. .. .36 2.3 Enzymatic decomposition of sugar-SIN1 conjugates. .40 x 2.4 Conclusion. .46 2.5 Experimental. .. .46 3 Design and synthesis of sialic acid-NO conjugates. .58 3.1 Introduction. .. .58 3.2 Design and synthesis of sialic acid-NO conjugates. .62 3.3 Hydrolysis of sialic acid/NO conjugates by sialidase. .68 3.4 Conclusion. .. .71 3.5 Experimental. .. .72 4 Synthesis of prodrugs of 5-fluorouracil. .80 4.1 Introduction. .. .80 4.2 Design and synthesis of FU and NO conjugates. .. .84 4.3 NO releasing and cytotoxicity of FU-NO conjugates. .87 4.4 Design and synthesis of carbohydrate-FU conjugates. .91 4.5 Conclusion. .. .98 4.6 Experimental. .99 5 Synthesis of carboxyl indazoles as NOS inhibitors. .112 5.1 Introduction. .. .112 5.2 Synthesis of carboxylindazoles . .114 5.3 Conclusion. .. .116 5.4 Experimental. .. .117 References. .120 Appendix: Selected NMR spectra. .129 xi LIST OF SCHEMES Scheme Page 1.1 Biological generation and functions of NO . 2 1.2 Synthetic methods of N-hydroxyguanidines . 6 1.3 Two modes of catalytic reactions of NOS . 14 1.4 Design and synthesis of N-isopropyl-N’-hydroxyarginine . 15 1.5 Proposed electrochemical oxidation of N-hydroxyguanidines . 19 2.1 NO releasing from SIN-1. 35 2.2 Synthesis of SIN-1. 36 2.3 Synthesis of glucose, galactose and SIN-1 conjugates . 38 2.4 Synthesis of galactose and GEA 3126 conjugate . 39 2.5 Synthesis of the phenol linkage on galactose . 40 2.6 Proposed NO releasing from 37b . 46 3.1 NO releasing from diazeniumdiolates . 59 3.2 Attempts to synthesize type I sialic acid-NO conjugates . 64 3.3 Attempts to synthesize type II sialic acid-NO conjugates. 65 3.4 Synthesis of sialic acid and SIN-1 conjugates . 67 3.5 Synthesis of sialic acid-diazeniumdiolate conjugates. ..
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