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An Approach for the Fragment-Based Drug Discovery of Anti-Alzheimer's BACE1 Inhibitors and NH-Assisted Fürst-Plattner Opening of Cyclohexene Oxides

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An Approach for the Fragment-Based Drug Discovery of Anti-Alzheimer's BACE1 Inhibitors and NH-Assisted Fürst-Plattner Opening of Cyclohexene Oxides Triazole-linked reduced amide isosteres: An approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors and NH-assisted Fürst-Plattner opening of cyclohexene oxides Christopher Jon Monceaux Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Chemistry Dr. Paul R. Carlier, Chairman Dr. Felicia A. Etzkorn Dr. Harry W. Gibson Dr. David G. I. Kingston Dr. Webster L. Santos December 9, 2010 Blacksburg, VA Keywords : Fürst-Plattner ( trans diaxial effect), epoxidation, epoxide opening, click-chemistry, diazotransfer, microtiter plate-based screening, reduced amide BACE1 inhibitors Copyright 2010, Christopher J. Monceaux Triazole-linked reduced amide isosteres: An approach for the fragment-based drug discovery of anti-Alzheimer's BACE1 inhibitors and NH-assisted Fürst-Plattner opening of cyclohexene oxides Christopher Jon Monceaux ABSTRACT In the scope of our BACE1 inhibitor project we used an originally designed microtiter plate-based screening to discover 4 triazole-linked reduced amide isosteres that showed modest (single digit micromolar) BACE1 inhibition. Our ligands were designed based on a very potent (single digit nanomolar) isopththalamide ligand from Merck. We supplanted one of the amide linkages in order to incorporate our triazole and saw a 1000-fold decrease in potency. We then enlisted Molsoft, L.L.C. to compare our ligand to Merck’s in silico to account for this discrepancy. They found that the triazole linkage gives rise to a significantly different docking pose in the active site of the BACE1 enzyme, therefore diminishing its potency relative to the Merck ligand. The ability to control the regio- and stereochemical outcome of organic reactions is an ongoing interest and challenge to synthetic chemists. The pre-association of reacting partners through hydrogen bonding (H-bonding) can often to yield products with extremely high stereoselectivity. We were able to show that anilines, due to their enhanced acidity relative to amines, can serve as substrate directing moieties in the opening of cyclohexene oxides. We observed that by judicious choice of conditions we could control the regiochemical outcome of the reaction. These studies demonstrate that an intramolecular anilino-NH hydrogen bond donor ii can direct Fürst-Plattner epoxide opening. A unified mechanism for this phenomenon has been proposed in this work which consists of a novel mechanistic route we call “NH-directed Fürst- Plattner.” We further studied the opening of cyclohexene oxides by incorporating amide and amide derivative substituents in both the allylic and homoallylic position relative to the epoxide moiety. Our attempts to control regioselectivity in the allylic systems were unsuccessful; however when the directing substituent was in the homoallylic position, we could demonstrate some degree of regioselectivity. An additional project that the author worked on for approximately one year during his graduate student tenure is not described within this work. In February of 2009 AstraZeneca, Mayo Clinic, and Virginia Tech Intellectual Properties Inc. concomitantly announced that AstraZeneca licensed a portfolio of preclinical Triple Reuptake Inhibitor (TRI) compounds for depression. The lead compound, PRC200, was discovered by a collaborative effort between the Carlier and Richelson (Mayo Clinic Jacksonville) research groups in 1998. The author was tasked to develop backup candidates of PRC200 in order to improve the pharmacokinetics of the lead compound. Due to confidentiality agreements, this work is not reported herein. iii Acknowledgements I would like to begin my acknowledgements by expressing my sincere gratitude to my advisor, Dr. Paul Carlier. The choice of a research advisor is one of the most important decisions one can make in their professional development; I certainly chose wisely. The time he took in order to give advice or talk chemistry whether it was in his office, on Skype, via IM, or even on his iPhone before boarding a flight is something that is truly unique to our research group. I will never forget doing molecular modeling together at a Starbucks in the Charlotte-Douglas International Airport. I am indebted to Dr. Carlier for ensuring that not only was I prepared to succeed as a Ph.D. chemist, but also for his efforts in attempting to secure me any professional position I wanted. I am looking forward to our new relationship and plan to seek his advice and counsel even in my professional career. I must also thank my Advisory Committee, Drs. Etzkorn, Dorn, Gibson, Kingston and Santos. Your advice and input has been indispensable during the course of my graduate career. Thanks must also be given to fellow graduate students, collaborators, and support staff that made the research described within this dissertation possible. I would like to express gratitude to the members of my research group during my tenure - Dr. Dawn Wong, Dr. Yiqun Zhang, Dr. Danny Hsu, Dr. Jason Harmon, Dr. Larry Williams, Dr. Nipa Deora, Josh Hartsel, Dr. Ming Ma, Yang Sheng Sun, Jenna Templeton, Madeline Nestor, Devin Rivers, Jonathan Meade, Ken Lui, Dr. Qiao-Hong Chen, Stephanie Bryson, Neeraj Patwardhan, Dr. Derek Craft, Astha, Zhenzhen Zhong and Rachel Davis. I would also like to thank Ken Knott from the Santos research group. The kilograms of caffeine we consumed along with the many total syntheses we completed in expo were an integral part of my graduate school experience. My collaborators iv Chiho Hirate-Fukae and Dr. Yasuji Matsuoka at Georgetown University Hospital also deserve thanks for their contributions to making the BACE1 project a reality. I would also like to thank Anton Sizovs and Qiao-Hong Chen for their help in translating journals from Russian and Chinese respectively. To conclude, I must give thanks to the people in my life outside the professional circle. I have to thank my Mother and Father who have been along since kindergarten and have now seen me through graduate school. Without your love, guidance, and support this endeavor would not have been possible. I must also thank my Mother and Father In-law, your support was invaluable and very much appreciated. And finally, my wife gets the greatest thanks of all. I am truly blessed to have you in my life – your love, patience, and unwavering encouragement throughout this process was truly precious to me. v Dedication To Tamara, without you none of this would have been possible. I love you. vi Table of Contents List of Schemes .......................................................................................................................... ix List of Figures ............................................................................................................................ xi List of Tables ............................................................................................................................. xii Chapter 1 Design, Synthesis, and Screening of Triazole Linked BACE1 Inhibitors ................... 1 1.1 Amyloid Beta Peptide Theory .............................................................................................. 1 1.2 β−Secretase as a drug target ................................................................................................. 3 1.3 Development of BACE1 drug like inhibitors ....................................................................... 5 1.3.1 Statine TSI ...................................................................................................................... 6 1.3.2 Hydroxyethylene TSI ..................................................................................................... 8 1.3.3 Lipinski’s Rule of Five and the Hydroxyethylamine TSI ............................................ 10 1.3.4 Reduced amide TSI ...................................................................................................... 15 1.3.5 1,2,3-Triazoles as amide surrogates ............................................................................ 19 1.4 Synthesis and screening of our 1,2,3-triazole containing inhibitors .................................. 20 1.4.1 Synthesis of acetylenes and azides .............................................................................. 20 1.4.2 CuAAC reaction .......................................................................................................... 26 1.4.3 The BACE1 FRET Assay ............................................................................................. 27 1.4.4 Microtiter Plate Based Screening ................................................................................ 30 1.4.5 Our Microtiter Plate Based Screening .......................................................................... 32 1.5 In silico docking of our triazole linked BACE1 inhibitors ................................................ 36 1.6 Conclusions from the Triazole linked BACE1 Inhibitor Project ........................................ 39 Chapter 2 Regioselective synthesis of aniline-derived 1,3- and C i-symmetric 1,4-diols from 1,4-trans-cyclohexadiene-dioxide and the synthesis of aniline-derived 1,3- and 1,2-Diols from 1,3-trans -cyclohexadiene-dioxide ..................................................................................... 40 2.1 Trans -diaxial effect or the Fürst-Plattner rule ..................................................................... 40 2.1.1 Applications of epoxides and arene oxides
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