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Synthesis and Antitumor Activities of Aquayamycin and Analogues Of A Dissertation entitled Synthesis and Antitumor Activities of Aquayamycin and Analogues of Derhodinosylurdamycin A and Synthesis of S-Linked Trisaccharide Glycal of Derhodinosylurdamycin A by Padam Prasad Acharya Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry ___________________________________________ Dr. Jianglong Zhu, Committee Chair ___________________________________________ Dr. Steven J. Sucheck, Committee Member ___________________________________________ Dr. Peter R. Andreana, Committee Member ___________________________________________ Dr. L. M. Viranga Tillekeratne, Committee Member ___________________________________________ Dr. Cyndee Gruden, Dean College of Graduate Studies The University of Toledo August 2019 © 2019 Padam Prasad Acharya This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Synthesis and Antitumor Activities of Aquayamycin and Analogues of Derhodinosylurdamycin A and Synthesis of S-Linked Trisaccharide Glycal of Derhodinosylurdamycin A by Padam Prasad Acharya Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry The University of Toledo August 2019 Angucycline natural antibiotics are one class of bioactive natural products which contain a tetracyclic ring frame assembled in an angular manner and are diversely glycosylated. These rapidly growing natural products exhibit diverse biological activities including enzymatic inhibitions, antitumor activities, antimicrobial activities, and platelet aggregation inhibition. The urdamycins are a subclass of angucyclines natural products and were first detected during the chemical screening of secondary metabolites produced by Streptomyces fradiae by Drautz and Co-workers in 1986. They are structurally related with an aquayamycin type of angucycline natural products which contains a C- glycosylated benz[a]anthraquinone core and a cis-diol at the ring junction. Urdamycins are bioactive natural products but the mode of action is unknown, therefore it would be appealing to prepare aquayamycin and analogs of derhodinosylurdamycin A for extensive SAR studies. Recently, we have completed the total syntheses of aquayamycin and analogues of derhodinosylurdamycin A with and without 2-deoxy sugar subunits. The synthesis was carried out on the basis of the convergent synthesis of derhodinosylurdamycin A as previously reported from our group. The mild cationic gold- iii catalyzed glycosylation with S-but-3-ynyl thioglycoside donors was employed for the synthesis of analogues bearing disaccharide subunits containing α-L-olivoside and α-L- olioside moiety, respectively. After the syntheses of these natural and unnatural compounds, we submitted aquayamycin, four different analogues, and our previously synthesized derhodinosylurdamycin A to the Development Therapeutics Program of the National Cancer Institute of National Institutes of Health for the NCI-60 Human Tumor Cell Lines Screening using standard protocols. It was found that the analogue bearing no sugar subunit demonstrates good potential for growth inhibition and cytotoxic activity against a variety of human cancer cell lines, however, aquayamycin, derhodinosylurdamycin A, and three other analogues bearing sugar subunits did not show significant antiproliferative activity against those human cancer cell lines. Thus we concluded that the sugar is not helpful to improve the anticancer activity of aquayamycin type of angucycline natural products. Derhodinosylurdamycin A, a bioactive natural product was discovered in 1989 by Zeeck et al., which was later found as the main urdamycin metabolite from S. fradiae Tü2717 mutant lacking UrdGT1a. Dehodinosylurdamycin A exhibits cytotoxic activity against L1210 leukemia cell lines (IC50 = 0.75 μg/mL). Structurally, it consists of tetracyclic aglycon core and a trisaccharide subunit connected via β-C-aryl glycosidic linkage. This trisaccharide subunit is composed of deoxy sugar subunits including two D- olivose and one L-rhodinose. Deoxy sugars are the important constituents of bioactive natural products, however, stereoselective synthesis of 2-deoxyglycosides remains a challenge due to lack of directing group at C2 position and are susceptible towards hydrolysis. Carbohydrate mimics such as S-linked glycosides are known to be resistant iv towards enzyme or acid-mediated hydrolysis. Therefore it is appealing to synthesize S- linked 2-deoxyglycosides. We successfully achieved the stereoselective synthesis of S- linked trisaccharide glycal of antitumor antibiotic derhodinosylurdamycin A. This synthesis was accomplished based on our group previously developed umpolung S- glycosylation strategy which utilizes the glycosyl lithium species for streoselective sulfenylation. We also found out that an alkyl thiocyanate is better electrophile than corresponding asymmetric disulfide for stereoselective sulfenylation of 2-deoxy glcosyl lithium. v This work is dedicated to my parents Mr. Tanka Prasad Acharya and Mrs. Nyaya Kumari Acharya. vi Acknowledgements My sincere gratitude goes to my advisor, Prof. Dr. Jianglong Zhu, for his sanguine support and constructive guidance since my first day in a laboratory. I sincerely appreciate his worthy of imitation training and encouragement that helped me to develop the proper skill required to conduct research. This attainment wouldn’t have been possible without his direction. I am grateful to the members of my research committee Prof. Dr. Steven J. Sucheck, Prof. Dr. Peter R. Andreana and Asso. Prof. Dr. L.M. Viranga Tillekeratne for their intuitive comments and valuable suggestions during my study. My thanks go to an undergraduate Sandip Janda whose hard work helped me to accomplish my project on time. I would also like to thank Dr. Kim for NMR and MS assistance. My previous and current lab members are the characters of admiration, the discussion with them was always fruitful. I thank the Department of Chemistry and Biochemistry, the University of Toledo for this opportunity. I would also like to appreciate NSF (CHE-1213352 and CHE-1464787) for partially funding my projects. My thanks also go to my parents and family members for their moral and emotional support so far. At last but not least, I am thankful to my wife Jiwan for her relentless support, care, and love throughout. vii Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ........................................................................................................... vii Table of Contents ............................................................................................................. viii List of Schemes .................................................................................................................. ix List of Tables ..................................................................................................................... xi List of Figures ................................................................................................................... xii List of Abbreviations ....................................................................................................... xiii Chapter 1 Synthesis and Antitumor Activities of Aquayamycin and Analogues of Derhodinosylurdamycin A 1.1 Background and Significance ...............................................................................1 1.1.1 Introduction of angucycline natural products ..............................................1 1.1.2 Urdamycin natural products .........................................................................3 1.1.3 Biological activities and mode of action of urdamycin natural products ....5 1.1.4 Earlier syntheses of aquayamycin type natural products .............................6 1.1.5 Analogues designed ...................................................................................10 1.2 Results and Discussion .........................................................................................10 1.2.1 Synthetic strategy .......................................................................................10 1.2.2 Synthesis of tetracyclic aryliodide .............................................................12 1.2.2.1 Synthesis of enantiopure epoxide and vinyl bromide ..........................12 viii 1.2.2.2 Synthesis of enone .........................................................................13 1.2.2.3 Synthesis of cyanophthalide ..........................................................14 1.2.2.4 Synthesis of tetracyclic aryliodide ......................................................15 1.2.3 Synthesis of aquayamycin..........................................................................16 1.2.3.1 Synthesis of glycal stannane ..........................................................16 1.2.3.2 Synthesis of aquayamycin..............................................................17 1.2.4 Synthesis of analogue A.............................................................................19 1.2.5 Synthesis of analogue B .............................................................................19 1.2.5.1 Synthesis of D-fucal derived glycal stannane ................................19 1.2.5.2 Synthesis of analogue B .................................................................20
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