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The Total Synthesis of Hexavalent Glycodendrimers

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The Total Synthesis of Hexavalent Glycodendrimers THE TOTAL SYNTHESIS OF HEXAVALENT GLYCODENDRIMERS USING A DIVERGENT PATHWAY FOR ANTI-HIV THERAPY A Thesis Presented to the faCulty of the Department of Chemistry California State University, SaCramento Submitted in partial satisfaCtion of the requirements for the degree of MASTER OF SCIENCE in Chemistry by Dustin Andres Dimas SUMMER 2018 © 2018 Dustin Andres Dimas ALL RIGHTS RESERVED ii THE TOTAL SYNTHESIS OF HEXAVALENT GLYCODENDRIMERS USING A DIVERGENT PATHWAY FOR ANTI-HIV THERAPY A Thesis by Dustin Andres Dimas Approved by: __________________________________, Committee Chair Dr. Katherine MCReynolds __________________________________, SeCond Reader Dr. Roy Dixon __________________________________, Third Reader Dr. Cynthia Kellen-Yuen ____________________________ Date iii Student: Dustin Andres Dimas I certify that this student has met the requirements for format contained in the University format manual, and that this thesis is suitable for shelving in the Library and credit is to be awarded for the thesis. __________________________, Graduate Coordinator ___________________ Dr. Susan Crawford Date Department of Chemistry iv AbstraCt of THE TOTAL SYNTHESIS OF HEXAVALENT GLYCODENDRIMERS USING A DIVERGENT PATHWAY FOR ANTI-HIV THERAPY by Dustin Andres Dimas The Human ImmunodefiCiency Virus (HIV) has caused a worldwide epidemiC. Currently, an estimated 36.9 million people are infeCted with HIV. The current treatment for HIV is antiretroviral therapy (ART). Around 20.9 million people living with HIV have aCCess to ART therapy. Right now, only 57% of the people infeCted are currently using ART. As of now, ART can only slow the progression of the virus but doesn’t cure the disease. Additionally, ART can have toxiC side effeCts or beCome ineffeCtive over time through viral resistance. This is why finding a way to prevent new HIV infeCtions is very important. A promising new Class of anti-HIV moleCules are dendrimers. All dendrimers have common charaCteristiCs: A core, linkers that increase the number of ends, and terminal functional groups where the chemistry can ocCur. For glycodendrimers, the functional groups can include amino, carboxyl or aminooxy moieties. In our research, the dendrimers terminate in aminooxy groups, whiCh can then reaCt chemoseleCtively with sugars to yield oxime-linked glycodendrimers. As dendrimers and glycodendrimers have v globular structures with multiple ends, they can exhibit the multivalent effeCt. Multivalency refers to the simultaneous interaCtions of multiple binding sites on one entity to multiple reCeptor sites on another. With this unique ability, sulfated glycodendrimers have been shown to bind to HIV virions and block fusion, and therefore the infeCtion, of host cells. Our research is focused on the synthesis of multivalent glycodendrimers as HIV entry inhibitors. In the present study, three diverse pathways were used to synthesize three hexavalent and one octavalent Core. After completing eaCh of the pathways, Cellobiose or the dimer of colominiC aCid was used to Create the desired terminated glycodendrimers. The purpose of the first pathway was to create a flexible hexavalent core. This pathway began by synthesizing the linkers for the hexavalent core. The reaCtion involved the addition of an aminooxy group on one end of the diols, either diethylene glycol (DEG) or 1,3-propandiol. Next, a methanesulfonyl group was added to the remaining OH to complete the linker synthesis. The seCond step in the process was to Create a trivalent Core to aCCept the linkers. Unfortunately, the linker would not reaCt with the Core so none of the desired product was obtained. The next pathway explored increasing the valency of the core by using an octavalent dendrimer core. This seCond pathway began by synthesizing a new linker for the octavalent Core. The first linker reaCtion involved the addition of an ether group to the linker. The seCond linker was synthesized to add the aminooxy group to the core. To make the tetravalent Core, the mesylated linker was added to the Core S under SN2 Conditions. Next, a three-step process was used to obtain the desired amine-terminated vi octavalent core. Finally, the addition of the aminooxy linker was added under carbamate Coupling. Unfortunately, it was not possible to aChieve the desired octavalent aminooxy- terminated dendrimer core, so no glycodendrimers could be made by this route. This study entailed the determination of two failed and one effeCtive route in synthesizing dendrimer cores. For the sucCessful hexavalent dendrimer core, a longer linker was synthesized to add an ether group with a yield of 99.8%. Additionally, through the synthesis of this linker it was determined that purifiCation methods of dialysis and FPLC were all that was needed to aChieve the best yield and time for purifiCation with 68.2%. Finally, for both the cellobiose and dimer of colominiC aCid glycodendrimers, the use of a smaller miCrowave cavity allowed for excellent yields of 77.8 and 79.2%, respeCtively. Further research needs to be conducted on this new core. The addition of more sugars, and further optimization of the yield of the hexavalent aminooxy terminated Core is needed. Future research will be Conducted to optimize the above steps, and finally to assess to the anti-HIV aCtivity of the sulfated products. _______________________, Committee Chair Dr. Katherine MCReynolds _______________________ Date vii ACKNOWLEDGEMENTS I would like to extend my sincere appreCiation and gratitude to those who have made Completion of this Thesis and my Master of SCience degree possible. First and foremost, I would like to thank my advisor Dr. Katherine MCReynolds, PhD. I would like to thank her for putting up with all my edits and shenanigans in lab. I also would like to thank her for seeing potential in me when I didn’t see it in myself. Without Dr. MCReynolds’ mentorship I would not have attempted a Master Program let alone pursued a PhD. I would like to thank my committee, Dr. Roy Dixon and Dr. Cynthia Kellen- Yuen, for dealing with my last minute edits before the deadline. I would also like to thank them for their open door poliCy whiCh allowed me to talk to either of them at any time about any issues I encountered along the way. I would also like to thank Dr. Jeff MaCk for helping me beCome the best teaCher I could be. He provided me with the opportunity to TA Chemistry 1A whiCh helped me deCide on a career pathway into teaChing. Next, I would like to thank my research group. I would like to extend my largest thanks to James Cerney. Lauren Wells, Juan Gonzalez, and Ugbad Farah, for helping me synthesize many compounds used throughout this entire projeCt. Without their help, it would have taken me months longer to finish my research. I would also like to thank GraCe Paragas, and Cory Vierra for just being there for me and allowing me to bounce ideas off them about edits on PowerPoints and my seminar. Additionally, I would like to thank all the other undergraduates who made coming to lab a joy through conversations and joking. They made whole group feel like a family. viii Finally, I would like to thank my family and friends. I appreCiate my parents’ understanding that I could not go home to San Jose for more than a few days while I worked in my lab. I would like to thank my girlfriend, Belinda Vue, for realizing that my lab work had to come before her most days and for helping me find a few distraCtions, like going to a movie or dinner, to take my mind off my research. I would like to thank my friends and family for visiting me when they knew I couldn’t get away to visit them. Finally, I would like to thank my great-grandparents. While they are no longer alive to see what I’ve aChieved, their value of education was passed own to me so that I could Complete a higher education. ix TABLE OF CONTENTS ACknowledgements ................................................................................................... viii List of Figures ............................................................................................................ xii List of SChemes ....................................................................................................... xviii Chapter 1. BACKGROUND .....................................................................................................1 HIV BaCkground ............................................................................................... 1 HIV-1 Life Cycle .............................................................................................. 2 Life Cycle of HIV-1 .......................................................................................... 6 Available Treatments for HIV .......................................................................... 8 NNRTI and NRTIs .......................................................................................... 11 INI Inhibitors .................................................................................................. 13 Protease inhibitors ........................................................................................... 14 CCR5 Inhibitor and Fusion Inhibitors ............................................................ 15 DrawbaCks of using ART ................................................................................ 18 Dendrimers ...................................................................................................... 24 Current Dendrimers ........................................................................................ 26
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