Co-reporter:Shiao Y. Chow and Adam Nelson
Journal of Medicinal Chemistry May 11, 2017 Volume 60(Issue 9) pp:3591-3591
Publication Date(Web):March 24, 2017
DOI:10.1021/acs.jmedchem.7b00423
The chemical space explored in drug discovery programs is restricted by a narrow reaction toolkit and the frequent failure of even these reactions with polar and functionalized substrates. Recently, high-throughput reaction optimization has been integrated into discovery workflows, thereby increasing the value of specific reaction classes in the toolkit. It is likely that high-throughput experimentation will enable expansion of the synthetic chemistry that is widely exploited in discovery, thereby increasing innovation in medicinal chemistry.
Co-reporter:Joan Mayol-Llinàs, Adam Nelson, William Farnaby, Andrew Ayscough
Drug Discovery Today 2017 Volume 22, Issue 7(Volume 22, Issue 7) pp:
Publication Date(Web):1 July 2017
DOI:10.1016/j.drudis.2017.01.008
•The potential of scaffolds to generate leads for CNS drug discovery is assessed.•Exemplar scaffolds have been prepared using a lead-oriented synthetic approach.•Priority scaffolds yield compounds aligned with CNS lead-generation needs.There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood–brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs. Prospective use of this CNS Lead Multiparameter Optimisation (MPO) scoring protocol can guide the further development of novel synthetic methodologies to access CNS-relevant and lead-like chemical space.Download high-res image (130KB)Download full-size image
Co-reporter:Joan Mayol-Llinàs;William Farnaby
Chemical Communications 2017 vol. 53(Issue 91) pp:12345-12348
Publication Date(Web):2017/11/14
DOI:10.1039/C7CC06078E
A modular synthetic approach was developed that yielded thirty diverse lead-like scaffolds suitable for CNS drug discovery.
Co-reporter:Chi H. Trinh;Alan Berry;Claire L. Windle;Katie J. Simmons;Arwen R. Pearson;James R. Ault
PNAS 2017 Volume 114 (Issue 10 ) pp:2431-2433
Publication Date(Web):2017-03-07
DOI:10.1073/pnas.1616816114
Natural enzymes are constructed from the 20 proteogenic amino acids, which may then require posttranslational modification
or the recruitment of coenzymes or metal ions to achieve catalytic function. Here, we demonstrate that expansion of the alphabet
of amino acids can also enable the properties of enzymes to be extended. A chemical mutagenesis strategy allowed a wide range
of noncanonical amino acids to be systematically incorporated throughout an active site to alter enzymic substrate specificity.
Specifically, 13 different noncanonical side chains were incorporated at 12 different positions within the active site of
N-acetylneuraminic acid lyase (NAL), and the resulting chemically modified enzymes were screened for activity with a range
of aldehyde substrates. A modified enzyme containing a 2,3-dihydroxypropyl cysteine at position 190 was identified that had
significantly increased activity for the aldol reaction of erythrose with pyruvate compared with the wild-type enzyme. Kinetic
investigation of a saturation library of the canonical amino acids at the same position showed that this increased activity
was not achievable with any of the 20 proteogenic amino acids. Structural and modeling studies revealed that the unique shape
and functionality of the noncanonical side chain enabled the active site to be remodeled to enable more efficient stabilization
of the transition state of the reaction. The ability to exploit an expanded amino acid alphabet can thus heighten the ambitions
of protein engineers wishing to develop enzymes with new catalytic properties.
Co-reporter:Ignacio Colomer, Christopher J. Empson, Philip Craven, Zachary Owen, Richard G. Doveston, Ian Churcher, Stephen P. Marsden and Adam Nelson
Chemical Communications 2016 vol. 52(Issue 45) pp:7209-7212
Publication Date(Web):05 May 2016
DOI:10.1039/C6CC03244C
Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.
Co-reporter:James D. Firth, Philip G. E. Craven, Matthew Lilburn, Axel Pahl, Stephen P. Marsden and Adam Nelson
Chemical Communications 2016 vol. 52(Issue 63) pp:9837-9840
Publication Date(Web):18 Jul 2016
DOI:10.1039/C6CC04662B
A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels–Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.
Co-reporter:Daniel J. Foley, Richard G. Doveston, Ian Churcher, Adam Nelson and Stephen P. Marsden
Chemical Communications 2015 vol. 51(Issue 56) pp:11174-11177
Publication Date(Web):11 May 2015
DOI:10.1039/C5CC03002A
A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space.
Co-reporter:Richard G. Doveston, Paolo Tosatti, Mark Dow, Daniel J. Foley, Ho Yin Li, Amanda J. Campbell, David House, Ian Churcher, Stephen P. Marsden and Adam Nelson
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 3) pp:859-865
Publication Date(Web):18 Nov 2014
DOI:10.1039/C4OB02287D
Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.
Co-reporter:Philip Craven, Anthony Aimon, Mark Dow, Nicolas Fleury-Bregeot, Rachel Guilleux, Remy Morgentin, Didier Roche, Tuomo Kalliokoski, Richard Foster, Stephen P. Marsden, Adam Nelson
Bioorganic & Medicinal Chemistry 2015 Volume 23(Issue 11) pp:2629-2635
Publication Date(Web):1 June 2015
DOI:10.1016/j.bmc.2014.12.048
The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and diplolar cycloadditions have been exploited as key steps. The synthesis of selected exemplar screening compounds is also described. In five cases, libraries were subsequently nominated for production on the basis of the scope and limitations of the validation work, as well as predicted molecular properties. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.
Co-reporter:Ignacio Colomer, Ololade Adeniji, George M. Burslem, Philip Craven, Martin Ohsten Rasmussen, Anthony Willaume, Tuomo Kalliokoski, Richard Foster, Stephen P. Marsden, Adam Nelson
Bioorganic & Medicinal Chemistry 2015 Volume 23(Issue 11) pp:2736-2740
Publication Date(Web):1 June 2015
DOI:10.1016/j.bmc.2015.01.058
The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds. For one scaffold, the synthesis of exemplar screening compounds was undertaken to demonstrate potential value in small molecule library production.
Co-reporter:Ho Yin Li, Joachim Horn, Amanda Campbell, David House, Adam Nelson and Stephen P. Marsden
Chemical Communications 2014 vol. 50(Issue 71) pp:10222-10224
Publication Date(Web):23 Jul 2014
DOI:10.1039/C4CC04940C
Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible.
Co-reporter:Thomas James, Paul MacLellan, George M. Burslem, Iain Simpson, J. Andrew Grant, Stuart Warriner, Visuvanathar Sridharan and Adam Nelson
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 16) pp:2584-2591
Publication Date(Web):10 Mar 2014
DOI:10.1039/C3OB42512F
Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.
Co-reporter:Martin Fisher, Ramkrishna Basak, Arnout P. Kalverda, Colin W. G. Fishwick, W. Bruce Turnbull and Adam Nelson
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 3) pp:486-494
Publication Date(Web):26 Nov 2013
DOI:10.1039/C3OB41975D
An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.
Co-reporter:Paul MacLellan and Adam Nelson
Chemical Communications 2013 vol. 49(Issue 24) pp:2383-2393
Publication Date(Web):16 Jan 2013
DOI:10.1039/C2CC38184B
Historically, chemists' exploration of chemical space has been exceptionally uneven and unsystematic. This feature article outlines a comprehensive conceptual framework that may be used to capture, analyse and plan synthetic approaches that may address this historically uneven exploration. Illustrative examples of synthetic approaches that target, or have potential to target, broad tracts of lead-like chemical space are presented within the context of this conceptual framework. Particular emphasis is placed on synthetic approaches that enable the combinatorial variation of molecular scaffold, particularly within the boundaries of lead-like chemical space.
Co-reporter:Thomas James, Iain Simpson, J. Andrew Grant, Visuvanathar Sridharan, and Adam Nelson
Organic Letters 2013 Volume 15(Issue 23) pp:6094-6097
Publication Date(Web):November 12, 2013
DOI:10.1021/ol402988s
Ring-opening of cyclic sulfamidates with propargylic sulfonamides yielded substrates for a gold-catalyzed cyclization to yield tetrahydropyrazines. Manipulation of the tetrahydropyrazines, by reduction or using multicomponent reactions, yielded piperazine scaffolds in which substitution of the carbon atoms was varied. Such scaffolds may have value in the synthesis of novel screening compounds with lead-like molecular properties.
Co-reporter:Catherine Joce, Rebecca White, Peter G. Stockley, Stuart Warriner, W. Bruce Turnbull, Adam Nelson
Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 1) pp:278-284
Publication Date(Web):1 January 2012
DOI:10.1016/j.bmcl.2011.11.017
In optimal cases, bivalent ligands can bind with exceptionally high affinity to their protein targets. However, designing optimised linkers, that orient the two binding groups perfectly, is challenging, and yet crucial in both fragment-based ligand design and in the discovery of bisubstrate enzyme inhibitors. To further our understanding of linker design, a series of novel bivalent S-adenosylmethionine (SAM) analogues were designed with the aim of interacting with the MetJ dimer in a bivalent sense (1:1 ligand/MetJ dimer). A range of ligands was synthesised and analyzed for ability to promote binding of the Escherichia coli methionine repressor, MetJ, to its operator DNA. Binding of bivalent SAM analogues to the MetJ homodimer in the presence of operator DNA was evaluated by fluorescence anisotropy and the effect of linker length and structure was investigated. The most effective bivalent ligand identified had a flexible linker, and promoted the DNA–protein interaction at 21-times lower concentration than the corresponding monovalent control compound.Figure optionsDownload full-size imageDownload as PowerPoint slide
Co-reporter:Sarah Murrison;Sushil K. Maurya;Christian Einzinger;Ben McKeever-Abbas;Stuart Warriner
European Journal of Organic Chemistry 2011 Volume 2011( Issue 12) pp:2354-2359
Publication Date(Web):
DOI:10.1002/ejoc.201100116
Abstract
A synthetic approach to skeletally diverse alkaloid-like compounds, involving two consecutive three-component reactions, was developed. First, reaction between a range of secondary amines, carbonyl compounds and triazines yielded cyclic imines. Crucially, the identity of the substituents in the amine and carbonyl compound components determined – through a “folding” pathway – the alkaloid-like scaffold that was prepared. The cyclic imine products were substrates for a second reaction, most usually a Joullié–Ugi reaction with an isocyanide and a carboxylic acid. Thus, the final products were, in general, ultimately derived from five separate components, and wide and independent variation of the substitution of each scaffold was possible. The 43 products were based on 28 distinct graph-node level frameworks. The high skeletal diversity of the products stemmed both from the “folding” pathway used to define the scaffolds of the cyclic imines, and from cyclic substituents used in each of the components.
Co-reporter:Paolo Tosatti, Amanda J. Campbell, David House, Adam Nelson, and Stephen P. Marsden
The Journal of Organic Chemistry 2011 Volume 76(Issue 13) pp:5495-5501
Publication Date(Web):May 12, 2011
DOI:10.1021/jo200720c
The sequential use of Cu-catalyzed asymmetric allylic alkylation, olefin cross-metathesis, and Ir-catalyzed asymmetric allylic amination allows the concise, stereodivergent synthesis of complex chiral amines with complete regiocontrol and good diastereoselectivity, exemplified by the synthesis of a pair of diastereoisomeric unnatural branched amino acid derivatives.
Co-reporter:Paolo Tosatti;Joachim Horn;Ama J. Campbell;David House;Stephen P. Marsden
Advanced Synthesis & Catalysis 2010 Volume 352( Issue 18) pp:3153-3157
Publication Date(Web):
DOI:10.1002/adsc.201000721
Abstract
The combination of an air-stable iridium catalyst and the dipolar aprotic solvent dimethyl sulfoxide (DMSO) allowed, for the first time, the systematic exploitation of highly polar, functionalized amines in asymmetric allylic substitutions: low molecular weight, sp3-rich chiral building blocks were obtained with physicochemical properties that will be valuable in the synthesis of lead-like small molecules.
Co-reporter:Catherine O'Leary-Steele Dr.;PalleJ. Pedersen;Thomas James;Thomas Lanyon-Hogg;Stuart Leach Dr.;Jerome Hayes Dr.
Chemistry - A European Journal 2010 Volume 16( Issue 31) pp:9563-9571
Publication Date(Web):
DOI:10.1002/chem.201000707
Abstract
Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels–Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to “reprogram” the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels–Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a “safety-catch” linker that we have developed. It was demonstrated that, in certain cases, Diels–Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.
Co-reporter:Heather K. Bone, Teresa Damiano, Stephen Bartlett, Alexis Perry, Julie Letchford, Yolanda Sanchez Ripoll, Adam S. Nelson, Melanie J. Welham
Chemistry & Biology 2009 Volume 16(Issue 1) pp:15-27
Publication Date(Web):30 January 2009
DOI:10.1016/j.chembiol.2008.11.003
The ability to propagate embryonic stem cells (ESCs) while maintaining their pluripotency is critical if their potential use in regenerative medicine is to be realized. The mechanisms controlling ESC self-renewal are under intense investigation, and glycogen synthase kinase 3 (GSK-3) has been implicated in regulating both self-renewal and differentiation. To clarify its role in ESCs we have used chemical genetics. We synthesized a series of bisindolylmaleimides, a subset of which inhibit GSK-3 in murine ESCs and robustly enhance self-renewal in the presence of leukemia inhibitory factor (LIF) and serum, but not in the absence of LIF. Importantly, these molecules appear selective for GSK-3 and do not perturb other signaling pathways regulating self-renewal. Our study clarifies the functional importance of GSK-3 in regulation of ESC self-renewal and provides tools for investigating its role further.
Co-reporter:Catherine Joce, Jamie Caryl, Peter G. Stockley, Stuart Warriner and Adam Nelson
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 4) pp:635-638
Publication Date(Web):2008/12/19
DOI:10.1039/B816495A
The efficient synthesis of a range of stable SAM mimetics, and their ability to promote the binding of the E. coli methionine repressor (MetJ) to its operator DNA, is described.
Co-reporter:Sarah Murrison;David Glowacki Dr.;Christian Einzinger Dr.;James Titchmarsh;Stephen Bartlett Dr.;Ben McKeever-Abbas Dr.;Stuart Warriner Dr.
Chemistry - A European Journal 2009 Volume 15( Issue 9) pp:2185-2189
Publication Date(Web):
DOI:10.1002/chem.200802127
Co-reporter:Joachim Horn, Ho Yin Li, Stephen P. Marsden, Adam Nelson, Rachel J. Shearer, Amanda J. Campbell, David House, Gordon G. Weingarten
Tetrahedron 2009 65(44) pp: 9002-9007
Publication Date(Web):
DOI:10.1016/j.tet.2009.06.103
Co-reporter:Christopher Cordier, Daniel Morton, Stuart Leach, Thomas Woodhall, Catherine O'Leary-Steele, Stuart Warriner and Adam Nelson
Organic & Biomolecular Chemistry 2008 vol. 6(Issue 10) pp:1734-1737
Publication Date(Web):10 Apr 2008
DOI:10.1039/B804769N
Diisopropylsilyl ethers were activated with N-bromosuccinimide, and reacted with a fluorous-tagged alcohol, to yield tethered substrates for ring-closing metathesis reactions.
Co-reporter:Daniel Morton Dr.;Stuart Leach Dr.;Christopher Cordier Dr.;Stuart Warriner Dr.
Angewandte Chemie International Edition 2008 Volume 48( Issue 1) pp:104-109
Publication Date(Web):
DOI:10.1002/anie.200804486
Co-reporter:Daniel Morton Dr.;Stuart Leach Dr.;Christopher Cordier Dr.;Stuart Warriner Dr.
Angewandte Chemie 2008 Volume 121( Issue 1) pp:110-115
Publication Date(Web):
DOI:10.1002/ange.200804486
Co-reporter:Karen Dodd;Daniel Morton Dr.;Stephen Worden Dr.;Robert Narquizian Dr.
Chemistry - A European Journal 2007 Volume 13(Issue 20) pp:
Publication Date(Web):25 APR 2007
DOI:10.1002/chem.200700277
The desymmetrisation of centrosymmetric molecules by enantioselective carbon–carbon bond formation has been reported for the first time. A bimetallic zinc catalyst developed by Trost was exploited in the desymmetrisation of a centrosymmetric dialdehyde. The approach was successful with a range of ketone nucleophiles and was uniformly highly diastereoselective (>98:<2). The yield and the enantioselectivity of the reaction varied as a function of the ketone used, and the desymmetrised products were obtained in up to 74 % yield and 97 % ee (ee=enantiomeric excess). The desymmetrisation of centrosymmetric molecules by enantioselective carbon–carbon bond formation is an efficient and convergent synthetic approach which is likely to find wide application in synthesis, particularly in the total synthesis of natural products with embedded centrosymmetric fragments.
Co-reporter:Christopher Cordier
ChemBioChem 2005 Volume 6(Issue 11) pp:
Publication Date(Web):18 OCT 2005
DOI:10.1002/cbic.200500250
Slipping through. Small molecules can give insight into the mechanisms controlled by proteins other than their direct molecular targets. A range of toxic compounds with diverse physicochemical properties has been used to investigate the quality of the outer-membrane barriers in E. coli strains, see graphic. A chemical genetic approach was used in combination with a forward classical genetic approach to identify some of the proteins involved in outer-membrane biogenesis.
Co-reporter:Thomas Woodhall;Gavin Williams Dr.;Alan Berry Dr. Dr.
Angewandte Chemie 2005 Volume 117(Issue 14) pp:
Publication Date(Web):2 MAR 2005
DOI:10.1002/ange.200462733
Erweiterte Substratspezifität: Eine modifizierte Form der Sialinsäure-Aldolase (E192N) hat eine 640fach höhere Substratspezifität als das Wildtyp-Enzym. Die Ozonolyse der ungesättigten Amide 1 und ein anschließender E192N-vermittelter Schritt wurden für die parallele Synthese von 14 Sialinsäuremimetika der allgemeinen Formel 2 genutzt.
Co-reporter:Simon Barrett;Stephen Bartlett;Ama Bolt;Alan Ironmonger;Catherine Joce ;Thomas Woodhall
Chemistry - A European Journal 2005 Volume 11(Issue 21) pp:
Publication Date(Web):1 AUG 2005
DOI:10.1002/chem.200500520
The bisindolylmaleimides are selective protein kinase inhibitors that can adopt two limiting diastereomeric (syn and anti) conformations. The configurational stability of a range of substituted and macrocyclic bisindolylmaleimides was investigated by using appropriate techniques. With unconstrained bisindolylmaleimides, the size of the 2-indolyl substituents was found to affect configurational stability, though not sufficiently to allow atropisomeric bisindolylmaleimides to be obtained. However, with a tether between the two indole nitrogen atoms in place, the steric effect of 2-indolyl substituents was greatly exaggerated, leading to large differences in configurational stability. The rate of interconversion of the syn and anti conformers varied by over twenty orders of magnitude through substitution of a bisindolylmaleimide ring system, which was constrained within a macrocyclic ring. Indeed, the first examples of configurationally stable atropisomeric bisindolylmaleimides are reported; the half-life for epimerisation of these compounds at room temperature was estimated to be >107 years.
Co-reporter:Thomas Woodhall;Gavin Williams Dr.;Alan Berry Dr. Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 14) pp:
Publication Date(Web):2 MAR 2005
DOI:10.1002/anie.200462733
Broadening substrate specificity: A modified form of sialic acid aldolase (E192N) exhibits a 640-fold switch in substrate specificity relative to the wild-type enzyme. Ozonolysis of the unsaturated amides 1, followed by an E192N-mediated step, was exploited in the parallel synthesis of 14 different sialic acid mimetics of general structure 2.
Co-reporter:Richard Doveston, Stephen Marsden, Adam Nelson
Drug Discovery Today (July 2014) Volume 19(Issue 7) pp:813-819
Publication Date(Web):1 July 2014
DOI:10.1016/j.drudis.2013.11.006
•Sourcing large numbers of lead-like molecules for screening is challenging.•General approaches to vary combinatorially lead-like scaffolds are rare.•Some recent approaches to ranges of lead-like scaffolds are described.•Diversity-oriented strategies might be adapted for lead-oriented synthesis.•A broader reaction toolkit will probably be needed for lead-oriented synthesis.Sourcing large numbers of lead-like molecules – compounds that would serve as good starting points for drug discovery programmes – is currently very challenging. The concept of lead-oriented synthesis has recently been articulated to capture the specific problem of preparing diverse small molecules with lead-like molecular properties. In this Feature, some methods that might be used to prepare lead-like molecular scaffolds are described, and presented in the context of diversity-oriented synthetic strategies that allow wide variation in molecular scaffold. It is concluded that the development of a wider toolkit of reactions that is reliable with more polar substrates will be required to allow genuine combination of molecular scaffold within lead-like chemical space.
Co-reporter:Claire L Windle, Alan Berry, Adam Nelson
Current Opinion in Chemical Biology (April 2017) Volume 37() pp:33-38
Publication Date(Web):April 2017
DOI:10.1016/j.cbpa.2016.12.029
Co-reporter:Amanda Bolt, Alan Berry, Adam Nelson
Archives of Biochemistry and Biophysics (15 June 2008) Volume 474(Issue 2) pp:318-330
Publication Date(Web):15 June 2008
DOI:10.1016/j.abb.2008.01.005
Co-reporter:James D. Firth, Philip G. E. Craven, Matthew Lilburn, Axel Pahl, Stephen P. Marsden and Adam Nelson
Chemical Communications 2016 - vol. 52(Issue 63) pp:NaN9840-9840
Publication Date(Web):2016/07/18
DOI:10.1039/C6CC04662B
A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels–Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.
Co-reporter:Ho Yin Li, Joachim Horn, Amanda Campbell, David House, Adam Nelson and Stephen P. Marsden
Chemical Communications 2014 - vol. 50(Issue 71) pp:NaN10224-10224
Publication Date(Web):2014/07/23
DOI:10.1039/C4CC04940C
Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible.
Co-reporter:Catherine Joce, Jamie Caryl, Peter G. Stockley, Stuart Warriner and Adam Nelson
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 4) pp:NaN638-638
Publication Date(Web):2008/12/19
DOI:10.1039/B816495A
The efficient synthesis of a range of stable SAM mimetics, and their ability to promote the binding of the E. coli methionine repressor (MetJ) to its operator DNA, is described.
Co-reporter:Christopher Cordier, Daniel Morton, Stuart Leach, Thomas Woodhall, Catherine O'Leary-Steele, Stuart Warriner and Adam Nelson
Organic & Biomolecular Chemistry 2008 - vol. 6(Issue 10) pp:NaN1737-1737
Publication Date(Web):2008/04/10
DOI:10.1039/B804769N
Diisopropylsilyl ethers were activated with N-bromosuccinimide, and reacted with a fluorous-tagged alcohol, to yield tethered substrates for ring-closing metathesis reactions.
Co-reporter:Richard G. Doveston, Paolo Tosatti, Mark Dow, Daniel J. Foley, Ho Yin Li, Amanda J. Campbell, David House, Ian Churcher, Stephen P. Marsden and Adam Nelson
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 3) pp:NaN865-865
Publication Date(Web):2014/11/18
DOI:10.1039/C4OB02287D
Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.
Co-reporter:Martin Fisher, Ramkrishna Basak, Arnout P. Kalverda, Colin W. G. Fishwick, W. Bruce Turnbull and Adam Nelson
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 3) pp:NaN494-494
Publication Date(Web):2013/11/26
DOI:10.1039/C3OB41975D
An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.
Co-reporter:Daniel J. Foley, Richard G. Doveston, Ian Churcher, Adam Nelson and Stephen P. Marsden
Chemical Communications 2015 - vol. 51(Issue 56) pp:NaN11177-11177
Publication Date(Web):2015/05/11
DOI:10.1039/C5CC03002A
A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space.
Co-reporter:Paul MacLellan and Adam Nelson
Chemical Communications 2013 - vol. 49(Issue 24) pp:NaN2393-2393
Publication Date(Web):2013/01/16
DOI:10.1039/C2CC38184B
Historically, chemists' exploration of chemical space has been exceptionally uneven and unsystematic. This feature article outlines a comprehensive conceptual framework that may be used to capture, analyse and plan synthetic approaches that may address this historically uneven exploration. Illustrative examples of synthetic approaches that target, or have potential to target, broad tracts of lead-like chemical space are presented within the context of this conceptual framework. Particular emphasis is placed on synthetic approaches that enable the combinatorial variation of molecular scaffold, particularly within the boundaries of lead-like chemical space.
Co-reporter:Ignacio Colomer, Christopher J. Empson, Philip Craven, Zachary Owen, Richard G. Doveston, Ian Churcher, Stephen P. Marsden and Adam Nelson
Chemical Communications 2016 - vol. 52(Issue 45) pp:NaN7212-7212
Publication Date(Web):2016/05/05
DOI:10.1039/C6CC03244C
Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.
Co-reporter:Thomas James, Paul MacLellan, George M. Burslem, Iain Simpson, J. Andrew Grant, Stuart Warriner, Visuvanathar Sridharan and Adam Nelson
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 16) pp:NaN2591-2591
Publication Date(Web):2014/03/10
DOI:10.1039/C3OB42512F
Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.
![Ethanamine, 2-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-](http://img.cochemist.com/ccimg/91600/91578-89-1.png)
![Ethanamine, 2-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-](http://img.cochemist.com/ccimg/91600/91578-89-1_b.png)
![[1,1'-Biphenyl]-2,2'-dimethanamine](http://img.cochemist.com/ccimg/70900/70898-14-5.png)
![[1,1'-Biphenyl]-2,2'-dimethanamine](http://img.cochemist.com/ccimg/70900/70898-14-5_b.png)
![Benzenesulfonamide, N-[2-(hydroxymethyl)phenyl]-4-nitro-](http://img.cochemist.com/ccimg/90400/90312-01-9.png)
![Benzenesulfonamide, N-[2-(hydroxymethyl)phenyl]-4-nitro-](http://img.cochemist.com/ccimg/90400/90312-01-9_b.png)
![1H-Pyrrole, 2,5-dihydro-1-[(2-nitrophenyl)sulfonyl]-](http://img.cochemist.com/ccimg/219600/219583-73-0.png)
![1H-Pyrrole, 2,5-dihydro-1-[(2-nitrophenyl)sulfonyl]-](http://img.cochemist.com/ccimg/219600/219583-73-0_b.png)
![Benzenesulfonamide, N-[1-(2-furanyl)pentyl]-4-methyl-, (±)-](http://img.cochemist.com/ccimg/134400/134340-65-1.png)
![Benzenesulfonamide, N-[1-(2-furanyl)pentyl]-4-methyl-, (±)-](http://img.cochemist.com/ccimg/134400/134340-65-1_b.png)
![Carbamic acid, [1-(3-pyridinyl)-4-pentenyl]-, 1,1-dimethylethyl ester](http://img.cochemist.com/ccimg/145100/145096-80-6.png)
![Carbamic acid, [1-(3-pyridinyl)-4-pentenyl]-, 1,1-dimethylethyl ester](http://img.cochemist.com/ccimg/145100/145096-80-6_b.png)
![Pyrrolidine, 1-[(1R,2R)-2-chlorocyclohexyl]-, rel-](http://img.cochemist.com/ccimg/20700/20698-68-4.png)
![Pyrrolidine, 1-[(1R,2R)-2-chlorocyclohexyl]-, rel-](http://img.cochemist.com/ccimg/20700/20698-68-4_b.png)
![MORPHOLINE, 4,4'-[(3E)-1,6-DIOXO-3-HEXENE-1,6-DIYL]BIS-](http://img.cochemist.com/ccimg/511600/511543-69-4.png)
![MORPHOLINE, 4,4'-[(3E)-1,6-DIOXO-3-HEXENE-1,6-DIYL]BIS-](http://img.cochemist.com/ccimg/511600/511543-69-4_b.png)
![2,2-DIMETHYL-5-VINYL-[1,3]DIOXOLANE-4-CARBOXYLIC ACID](http://img.cochemist.com/ccimg/100000/99902-66-6.png)
![2,2-DIMETHYL-5-VINYL-[1,3]DIOXOLANE-4-CARBOXYLIC ACID](http://img.cochemist.com/ccimg/100000/99902-66-6_b.png)
![1H-Indole,3,3'-[(2S,5R)-1-methyl-2,5-piperazinediyl]bis[6-bromo-](http://img.cochemist.com/ccimg/128400/128364-31-8.png)
![1H-Indole,3,3'-[(2S,5R)-1-methyl-2,5-piperazinediyl]bis[6-bromo-](http://img.cochemist.com/ccimg/128400/128364-31-8_b.png)
![[2,2'-Bifuran]-5,5'(2H,2'H)-dione, tetrahydro-, (2R,2'S)-rel-](http://img.cochemist.com/ccimg/55000/54933-62-9.png)
![[2,2'-Bifuran]-5,5'(2H,2'H)-dione, tetrahydro-, (2R,2'S)-rel-](http://img.cochemist.com/ccimg/55000/54933-62-9_b.png)
![2-Cyclopenten-1-ol, 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-, acetate,(1R,4S)-](http://img.cochemist.com/ccimg/115100/115074-49-2.png)
![2-Cyclopenten-1-ol, 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-, acetate,(1R,4S)-](http://img.cochemist.com/ccimg/115100/115074-49-2_b.png)
![Oxepino[3,2-b]pyrano[2',3':5,6]pyrano[2,3-f]oxepin-2-propanal,9-(3Z)-3,5-hexadien-1-ylhexadecahydro-4,10-dihydroxy-5a,10-dimethyl-a-methylene-,(2R,4S,4aS,5aR,7aS,9R,10S,12aR,13aS,14aR)-](http://img.cochemist.com/ccimg/122300/122271-91-4.png)
![Oxepino[3,2-b]pyrano[2',3':5,6]pyrano[2,3-f]oxepin-2-propanal,9-(3Z)-3,5-hexadien-1-ylhexadecahydro-4,10-dihydroxy-5a,10-dimethyl-a-methylene-,(2R,4S,4aS,5aR,7aS,9R,10S,12aR,13aS,14aR)-](http://img.cochemist.com/ccimg/122300/122271-91-4_b.png)
![bis[(2,3,5,6-η)-bicyclo[2.2.1]hepta-2,5-diene]di-μ-chlorodirhodium](http://img.cochemist.com/ccimg/12300/12257-42-0.png)
![bis[(2,3,5,6-η)-bicyclo[2.2.1]hepta-2,5-diene]di-μ-chlorodirhodium](http://img.cochemist.com/ccimg/12300/12257-42-0_b.png)
![Bicyclo[5.1.0]octane, 8,8-dibromo-, cis-](http://img.cochemist.com/ccimg/52800/52750-35-3.png)
![Bicyclo[5.1.0]octane, 8,8-dibromo-, cis-](http://img.cochemist.com/ccimg/52800/52750-35-3_b.png)
![2-Butenoic acid, 4-[[(1,1-dimethylethoxy)carbonyl]amino]-, ethyl ester,(2E)-](http://img.cochemist.com/ccimg/104800/104700-36-9.png)
![2-Butenoic acid, 4-[[(1,1-dimethylethoxy)carbonyl]amino]-, ethyl ester,(2E)-](http://img.cochemist.com/ccimg/104800/104700-36-9_b.png)
![Benzaldehyde,4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-](http://img.cochemist.com/ccimg/160800/160744-60-5.png)
![Benzaldehyde,4-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-](http://img.cochemist.com/ccimg/160800/160744-60-5_b.png)
![Carbamic acid,N-[(2R)-2,3-dihydroxypropyl]-, 1,1-dimethylethyl ester](http://img.cochemist.com/ccimg/149000/148983-23-7.png)
![Carbamic acid,N-[(2R)-2,3-dihydroxypropyl]-, 1,1-dimethylethyl ester](http://img.cochemist.com/ccimg/149000/148983-23-7_b.png)
![2-{[2-(TRIFLUOROMETHYL)BENZYL]OXY}-1H-ISOINDOLE-1,3(2H)-DIONE](http://img.cochemist.com/ccimg/70400/70326-81-7.png)
![2-{[2-(TRIFLUOROMETHYL)BENZYL]OXY}-1H-ISOINDOLE-1,3(2H)-DIONE](http://img.cochemist.com/ccimg/70400/70326-81-7_b.png)
![7-oxabicyclo[4.1.0]hept-3-ene](http://img.cochemist.com/ccimg/6300/6253-27-6.png)
![7-oxabicyclo[4.1.0]hept-3-ene](http://img.cochemist.com/ccimg/6300/6253-27-6_b.png)
![4,8-dioxatricyclo[5.1.0.03,5]octane](http://img.cochemist.com/ccimg/16100/16063-09-5.png)
![4,8-dioxatricyclo[5.1.0.03,5]octane](http://img.cochemist.com/ccimg/16100/16063-09-5_b.png)
![4,8-dioxatricyclo[5.1.0.03,5]octane](http://img.cochemist.com/ccimg/16100/16063-08-4.png)
![4,8-dioxatricyclo[5.1.0.03,5]octane](http://img.cochemist.com/ccimg/16100/16063-08-4_b.png)
![9-((3AR,4R,6R,6AR)-2,2-DIMETHYL-6-((METHYLAMINO)METHYL)-TETRAHYDROFURO[3,4-D][1,3]DIOXOL-4-YL)-9H-PURIN-6-AMINE](http://img.cochemist.com/ccimg/34300/34245-49-3.png)
![9-((3AR,4R,6R,6AR)-2,2-DIMETHYL-6-((METHYLAMINO)METHYL)-TETRAHYDROFURO[3,4-D][1,3]DIOXOL-4-YL)-9H-PURIN-6-AMINE](http://img.cochemist.com/ccimg/34300/34245-49-3_b.png)
![3,11a-Epidithio-11aH-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-dione,2,3,5a,6,10b,11-hexahydro-3-(hydroxymethyl)-10b-[(1S,4S)-3-[[4-(hydroxymethyl)-5,7-dimethyl-6,8-dioxo-2,3-dithia-5,7-diazabicyclo[2.2.2]oct-1-yl]methyl]-1H-indol-1-yl]-2-methyl-,(3S,5aR,10bS,11aS)-](http://img.cochemist.com/ccimg/1500/1403-36-7.png)
![3,11a-Epidithio-11aH-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-dione,2,3,5a,6,10b,11-hexahydro-3-(hydroxymethyl)-10b-[(1S,4S)-3-[[4-(hydroxymethyl)-5,7-dimethyl-6,8-dioxo-2,3-dithia-5,7-diazabicyclo[2.2.2]oct-1-yl]methyl]-1H-indol-1-yl]-2-methyl-,(3S,5aR,10bS,11aS)-](http://img.cochemist.com/ccimg/1500/1403-36-7_b.png)
![Ethanol,2-[(triphenylmethyl)thio]-](http://img.cochemist.com/ccimg/29200/29167-28-0.png)
![Ethanol,2-[(triphenylmethyl)thio]-](http://img.cochemist.com/ccimg/29200/29167-28-0_b.png)
![N-[BIS(FURAN-2-YL)METHYL]-4-METHYLBENZENESULFONAMIDE](http://img.cochemist.com/ccimg/488800/488720-06-5.png)
![N-[BIS(FURAN-2-YL)METHYL]-4-METHYLBENZENESULFONAMIDE](http://img.cochemist.com/ccimg/488800/488720-06-5_b.png)
![2-Propen-1-ol, 2-[[[(1,1-dimethylethyl)diphenylsilyl]oxy]methyl]-](http://img.cochemist.com/ccimg/177700/177606-51-8.png)
![2-Propen-1-ol, 2-[[[(1,1-dimethylethyl)diphenylsilyl]oxy]methyl]-](http://img.cochemist.com/ccimg/177700/177606-51-8_b.png)
![Chromium,chloro[[2,2'-[(1R,2R)-1,2-cyclohexanediylbis[(nitrilo-kN)methylidyne]]bis[4,6-bis(1,1-dimethylethyl)phenolato-kO]](2-)]-, (SP-5-13)-](http://img.cochemist.com/ccimg/165000/164931-83-3.png)
![Chromium,chloro[[2,2'-[(1R,2R)-1,2-cyclohexanediylbis[(nitrilo-kN)methylidyne]]bis[4,6-bis(1,1-dimethylethyl)phenolato-kO]](2-)]-, (SP-5-13)-](http://img.cochemist.com/ccimg/165000/164931-83-3_b.png)
![N-[4-(1H,1H,2H,2H-PERFLUORODECYL)BENZYLOXYCARBONYLOXY]SUCCINIMIDE](http://img.cochemist.com/ccimg/356100/356056-15-0.png)
![N-[4-(1H,1H,2H,2H-PERFLUORODECYL)BENZYLOXYCARBONYLOXY]SUCCINIMIDE](http://img.cochemist.com/ccimg/356100/356056-15-0_b.png)
![Adenosine,5'-[[(3S)-3-amino-3-carboxypropyl]methylamino]-5'-deoxy- (9CI)](http://img.cochemist.com/ccimg/111800/111770-79-7.png)
![Adenosine,5'-[[(3S)-3-amino-3-carboxypropyl]methylamino]-5'-deoxy- (9CI)](http://img.cochemist.com/ccimg/111800/111770-79-7_b.png)
