University of Groningen Development and Application of Novel Scaffolds In

University of Groningen Development and application of novel scaffolds in drug discovery Boltjes, André DOI: 10.33612/diss.98161351 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Boltjes, A. (2019). Development and application of novel scaffolds in drug discovery: the MCR approach. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.98161351 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). 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Download date: 11-10-2021 DEVELOPMENT AND APPLICATION OF NOVEL SCAFFOLDS IN DRUG DISCOVERY The MCR approach André Boltjes The research described in this thesis was carried out at the Department of Drug Design (Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands) and was financially supported by the University of Groningen. Printing of this thesis was financially supported by the University Library and the Graduate School of Science, Faculty of Science and Engineering, University of Groningen, The Netherlands ISBN: 978-94-034-2005-9 (printed version) ISBN: 978-94-034-2004-2 (electronic version) Printing: Ipskamp printing, Enschede Cover design: André Boltjes Cover Graphics: By pikisuperstar Source: Freepik Copyright © 2019 André Boltjes. All rights are reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without the prior permission in writing of the author. Development and application of novel scaffolds in Drug Discovery The MCR approach Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op vrijdag 29 november 2019 om 14.30 uur door André Boltjes geboren op 10 april 1984 te Wieringermeer Promotores Prof. dr. A.S.S. Dömling Prof. dr. F.J. Dekker Beoordelingscommissie Prof. dr. R.V.A Orru Prof. dr. G.J. Poelarends Prof. dr. ir. A.J. Minnaard Table of Contents CHAPTER 1 GENERAL INTRODUCTION 1 CHAPTER 2 FRAGMENT BASED LIBRARY GENERATION FOR 11 THE DISCOVERY OF A PEPTIDOMIMETIC P53-MDM4 INHIBITOR CHAPTER 3 UGI MULTICOMPONENT APPROACH TO 35 SYNTHESIZE SCHISTOSOMIASIS DRUG PRAZIQUANTEL CHAPTER 4 UGI 4-CR SYNTHESIS OF γ- AND δ-LACTAMS 51 PROVIDING NEW ACCESS TO DIVERSE ENZYME INTERACTIONS, A PDB ANALYSIS CHAPTER 5 Gd-TEMDO: DESIGN, SYNTHESIS AND MRI 75 APPLICATION CHAPTER 6 THE GROEBKE-BLACKBURN-BIENAYMÉ 97 REACTION CHAPTER 7 DIVERSE ONE-POT SYNTHESIS OF ADENINE 189 MIMETICS FOR BIOMEDICAL APPLICATIONS CHAPTER 8 SUMMARY AND DISCUSSION 213 SAMENVATTING NEDERLANDSE SAMENVATTING 223 APPENDIX ACKNOWLEDGEMENTS 231 LIST OF PUBLICATIONS ABOUT THE AUTHOR Chapter 1 Introduction MCR introduction, Perspective and Outline Chapter 1 Multicomponent reactions Multicomponent reactions (MCRs) are a special class of chemical transforma- tions, which produce complex scaffolds in a single step by employing three or more starting materials, in which most of the atoms are present in the final product.1 This type of chemistry can be classified as a domino reaction. Similar to polymer chemistry, MCRs proceed through a cascade of intermediate reactions, however, yielding a complex but small molecule. The first example of a MCR reaction is the Strecker amino acid synthesis, developed almost 170 years ago in 1850. The Strecker reaction is a 3-component reaction (3-CR) between an aldehyde or ketone, ammonia and potassium cyanide and yields an α-aminonitrile, subsequent hydrolysis gives access to synthetic α-amino acids (Scheme 1).2 The high atom economy, efficiency, convergent nature and very high bond forming index of MCR reactions make this class extremely useful for drug exploration.3 O R + NH3 + KCN R H H2N COOH Scheme 1. The Strecker amino acid synthesis. MCRs are often considered to be complex, because the formation of the final products proceed via a number of intermediate steps. In order to understand the complex nature of MCRs, a breakdown of the reaction into intermediate steps could aid in comprehension of the underlying mechanism. Difference in reactivity of each of the individual components is the driving force behind selective reactions, resulting in a predefined order in which each component will react. The most common studied and therefore well-developed early type of MCRs evolve around the reactivity of imine groups, usually obtained through reacting carbonyl compounds with amines. The resulting imines or Schiff bases are electrophiles and can react via electrophilic addition to for example α-methylene carbonyls in the Mannich 3-CR, to β-ketoesters in the Biginelli 3-CR, to boronates (from boronic acids) in the Petasis 3-CR and many other reactions, described in scheme 2.4-8 The formation of the Schiff base is performed in the presence of the third component, the electrophile, in a one-pot fashion, which in practice comes down to adding all the reactants together in a suitable solvent and stir the multicomponent reaction, often under ambient conditions. The selective order generally allows for a clean reaction with little byproducts and high conversion towards a single product. 1 Introduction O R1 R2 NH Strecker + 2 + HCN R3 R3 N CN R1 R2 H 1 R3 R4 O O H O Mannich + N + R1 R R R5 N R6 R3 R4 1 2 R6 R2 R5 O R1 O O O O Hantsch + NH2 + 2 R2 R1 H N R2 O R O O 3 Staudinger + NH2 + R2 R3 N R1 H Cl R2 R1 R R O H 1 4 Petasis + N + B(OH)2 R H R2 R3 R4 N 1 R2 R3 O Ar O O O O EtO NH Biginelli + + Ar H H2N NH2 EtO H3C N O H Scheme 2. Overview of the most common MCR 3-CR of amines, carbonyl compounds and nucleophiles. In 1920, Passerini discovered the first isocyanide based MCR reaction (IMCR) and involves an isocyanide, an oxo component and a nucleophile.9 The carbene like properties of the isocyanide group allow for some very interesting transfor- mations, as this functional group can behave as nucleophile and then as electrophile at the same atom, resulting to the so-called α-adduct.10 The IMCR subclass has complemented the field of MCR due to its versatile reactivity, variability and scaffolds and is currently the most widely used/applied type of MCR. Neverthe- less it took roughly 40 years until more developments were made in this field, which can be attributed to the obnoxious smell of the isocyanides. The smell is 2 Chapter 1 considered unpleasant, even in such a way that the US government investigated the use of isocyanides as non-lethal chemical weapons.11 The considered ‘con- straint’ is limited to the liquid isocyanides, as higher molecular weight isocyanides are often solid and have little to no smell. Regardless of this fact, the result is poor commercial availability, which is not necessarily problematic as isocyanides can readily be prepared from primary amines or aldehydes in one or two steps.12-14 O O O R1 R2 H Passerini-3CR + + NC N R4 R3 O R4 1920 R1 R2 R3 OH O O R R O O 1 2 H + NH2 + + NC N Ugi-4CR R3 R5 R4 N R5 1959 R1 R2 R4 OH R3 O H R1 R2 O H NC N R4 Ugi-3CR + N + R N R R R5 5 1959 R1 R2 3 4 O R3 R1 R2 R5 O H + + + NC R3 N Ugi Tetrazole-4CR N HN3 N R R R5 N 1959 R1 R2 3 4 R4 N N R O Ts 2 N N + NH + Van Leusen-3CR R 2 1977 R H 2 R NC 1 3 R1 R3 HN R2 Groebke Blackburn O 5- N + + NC N 6- R2 5- Bienaymè-3CR R1 R1 H NH2 6- 1998 N Scheme 3. Some of the well-known IMCRs A considerable amount of pioneering work with IMCRs was performed by Ugi in the late 1950s. The Ugi-4CR is defined as the reaction of an amine with an aldehyde or ketone, an isocyanide and a carboxylic acid (Scheme 3).15 The limits of IMCRs were explored by Ivar Ugi and since the introduction of the Ugi 4-CR, many new IMCR reactions have found their way to the nowadays well accept- 3 Introduction ed field of MCR chemistry. The work described in this thesis is based on drug design, utilizing the Ugi reaction and several variations of the Ugi reaction to synthesize drug like compounds and medical probes. 1 Drug discovery and MCR. Identification of biochemical pathways related to a disease and the intervention of potential targets is the first step in the discovery of new medicines.

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