Library Synthesis of Anticancer and Antibacterial Agents via Azide Chemistry

728 Pages·2017·9.26 MB·English

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All Graduate Theses and Dissertations Graduate Studies
5-2010
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Jianjun Zhang
Utah State University
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Library Synthesis of Anticancer and Antibacterial
Agents via Azide Chemistry
Jianjun Zhang
Utah State University
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Zhang, Jianjun, "Library Synthesis of Anticancer and Antibacterial Agents via Azide Chemistry" (2010).All Graduate Theses and
Dissertations.Paper 711.
http://digitalcommons.usu.edu/etd/711
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LIBRARY SYNTHESIS OF ANTICANCER AND ANTIBACTERIAL
AGENTS VIA AZIDE CHEMISTRY
by
Jianjun Zhang

A dissertation submitted in partial fulfillment
of the requirements for the degree
of
DOCTOR OF PHILOSOPHY
in
Chemistry
Approved

Cheng-Wei Tom Chang, Ph.D. Alvan C. Hengge, Ph.D.
Major Professor Committee Member

Bradley S. Davidson, Ph.D. Robert S. Brown, Ph.D.
Committee Member Committee Member

Jon Y. Takemoto, Ph.D. Byron Burnham
Committee Member Dean of Graduate Studies

UTAH STATE UNIVERSITY
Logan, Utah

2010
ii

Copyright © Jianjun Zhang 2010
All Rights Reserved
iii
ABSTRACT
Library Synthesis of Anticancer and Antibacterial Agents via Azide Chemistry
by
Jianjun Zhang, Doctor of Philosophy
Utah State University, 2010

Major Professor: Dr. Cheng-Wei Tom Chang
Department: Chemistry and Biochemistry

Various anticancer and antibacterial agents have been synthesized via azide
chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14
glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of
carbohydrate-cyclopamine conjugates with biological interests were synthesized based
on a highly efficient “click reaction” assisted by sonication. Some of the conjugates
have improved solubility and enhanced anticancer activity.
A library of neomycin B derivatives with various modifications at the 5′′ position
has been synthesized. Two leads exhibit prominent activity against both
methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant
enterococci (VRE). Antibacterial activities were measured when combined with other
clinically used antibiotics and significant synergistic activities were observed.
Three different classes of aryl N-glycosides have been synthesized by employing
1,4-naphthoquinone and glycosyl azides undergoing a [2+3] cycloaddition. Alkyl
iv
azides can also undergo the same cycloaddition. After the removal of the protecting
group, a library of 9,10-anthraquinone derivatives with potential anticancer activity and
a library of 2-aminomethylene-1,3-indanediones with novel antibacterial activity have
been developed, respectively.
A one-pot three-component [2+3] cycloaddition for the synthesis of 1-alkyl
1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and 2-alkyl 2H-naphtho[2,3-d][1,2,3]
triazole-4,9-dione has been developed. By taking the advantage of their difference in
basicity, both products can be obtained in good purity.
Using an allylic azide rearrangement, a convenient method has been developed for
the synthesis of several 2',3'-dideoxyaminoglycosides. The antibacterial activity of
these novel aminoglycosides also confirms the indispensable role of the 2'-NH group
2
for both neomycin and kanamycin classes of aminoglycosides. A novel structural motif
containing the hexylaminocarbonyl groups at O-5 and/or O-6 of 2',3'-dideoxyneamine
could lead to the production of new aminoglycosides against resistant bacteria.

(726 pages)
v
ACKNOWLEDGMENTS

First of all, I’d like to express my sincere appreciation to my supervisor, Dr.
Cheng-wei Tom Chang, for his continuous assistance, guidance, and support during my
graduate study. He really taught me a lot in experimental technologies and scientific
ideas, and every way of working as an organic chemist. He has been approachable and
easy to talk to on every research problem. I own my current and future success to him.
Dr. Chang’s contribution is greatly appreciated and it has been so much pleasure having
him as my mentor. Thanks, Tom.
Besides my advisor, I am also indebted to my supervisory committee for all their
assistances and instructions. I’d like to thank Dr. Alvan Hengge for his teaching me
organic chemistry and biochemistry and also his good advice on my graduate study. I’d
like to thank Dr. Jon Takemoto for his help in my research and his many
encouragements. I’d like to thank Dr. Bradley Davidson and Dr. Robert Brown for their
insightful comments and suggestions. Without their help, I could not have made
progress to finish my dissertation.
Secondly, I would also like to thank my “shi xiong” and his wife, Jie Li and Jinhua
Wang, for teaching me so many skills and helping me through the everyday life abroad.
I want to also thank my former lab mates, Ravi Rai, Christabel T. Tanifum, Yi Liang,
Fang-I Chiang, and Hsiao-Nung Chen, for their help and also many good memories of
working with them, thank my co-workers Marina Fosso, Anthony Litke, and Katherine
Keller for the good times in the lab. We did have fun in working together as a team.
vi
I would like to thank Dr. Vernon D. Parker, Dr. Scott A. Ensign, and Dr. Lisa M.
Berreau for their help. I would like to thank Dr. Jixun Zhan’s group for doing HPLC
analysis of my compounds. I would also like to thank Maribeth Evensen-Hengge for
her help to my family. Without their assistance, I could not go through my graduate
study smoothly.
Last, I must thank my family especially my loving wife, Caixia Xu. She always
takes most of the housework and encourages me to spend most of the time in my
research. It is her understanding and encouraging that support me to work efficiently
every day. My achievements make her even happier than myself. I wish to say thank
you to her for being a wonderful wife and mom. I am also indebted to my four parents
for their support in all these years. And I will not forget to express my appreciation to
my loving daughter, Fiona Xingyao Zhang, who really has given me much pleasure in
my life.

Jianjun Zhang
vii
CONTENTS
Page
ABSTRACT.................................................................................................................iii
ACKNOWLEDGMENTS.............................................................................................v
LIST OF TABLES.....................................................................................................viii
LIST OF FIGURES.......................................................................................................x
LIST OF SCHEMES.....................................................................................................xi
LIST OF SPECTRA....................................................................................................xii
LIST OF ABBREVIATIONS....................................................................................xliv
CHAPTER.....................................................................................................................1
I. GENERAL INTRODUCTION....................................................................1
II. SONICATION-ASSISTED LIBRARY SYNTHESIS OF
OXAZOLIDINONE-CARBOHYDRATE CONJUGATES.....................21

III. SYNTHESIS AND ANTICANCER ACTIVITY STUDIES OF
CYCLOPAMINE DERIVATIVES...........................................................31
IV. SYNTHESIS OF 5” MODIFIED NEOMYCIN AND ANTIBACTERIAL
ACTIVITY AGAINST RESISTANT BACTERIA...................................37
V. DIVERGENT SYNTHESIS OF THREE CLASSES OF ARYL
N-GLYCOSIDES BY SOLVENT CONTROL.........................................58

VI. ONE-POT SYNTHESIS OF 1- AND 2-SUBSTITUTED
NAPHTHO[2,3-d][1,2,3]TRIAZOLE-4,9-DIONES.................................74

VII. SYNTHESIS OF NOVEL AMINOGLYCOSIDES VIA ALLYLIC AZIDE
REARRANGEMENT................................................................................86

VIII. CONCLUSIONS AND OVERALL SIGNIFICANCE..............................99
IX. EXPERIMENTAL SECTION.................................................................103
REFERENCES..........................................................................................................201
APPENDIX................................................................................................................217
CURRICULUM VITAE............................................................................................678
viii

LIST OF TABLES

Table Page
1. Yields and ratios of stereisomers.......................................................................33

2. Anticancer activity of carbohydrate-cyclopamine conjugates against lung
cancer..................................................................................................................36

3. Yields and structure designs of class I 5”-modified neomycin derivatives.......40
4. Yields and structure designs of class II 5”-modificed neomycin derivatives....41
5. MIC of the 5”-modified neomycin derivatives (Unit: μg/mL)..........................44

6. Kinetic parameters and MIC of aminoglycosides against E. Coli (TG1) with
APH(3’)-IIIa (Unit: μg/mL)................................................................................46

7. MIC of the 5”-modified neomycin derivatives against other strains of bacteria
(Unit: μg/mL)......................................................................................................50

8. MIC of the 5”-acyl modified neomycin derivatives (Unit: μg/mL)...................52
9. FIC from combinational studies of 32b.............................................................56
10. Cycloaddition of naphthoquinone and azides..................................................63
11. Deprotection of 66...........................................................................................65
12. Deprotection of 69...........................................................................................66
13. Investigation of the effect of TMSOTf and the potential oxidant....................68
14. One-Pot Synthesis of 1-Alkyl 1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione...76
15. One-pot reaction with different electrophiles..................................................79
16. One pot reaction in toluene..............................................................................84