Imperial College London

ProfessorAlanArmstrong

Faculty of Natural SciencesDepartment of Chemistry

Professor of Organic Synthesis
 
 
 
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Contact

 

+44 (0)20 7594 5876a.armstrong

 
 
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Location

 

501EMolecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
to

137 results found

Muhieddine MH, Viswanath SK, Armstrong A, Galindo A, Adjiman CSet al., 2022, Model-based solvent selection for the synthesis and crystallisation of pharmaceutical compounds, CHEMICAL ENGINEERING SCIENCE, Vol: 264, ISSN: 0009-2509

Journal article

Zhong Z, Chesti J, Armstrong A, Bull Jet al., 2022, Synthesis of Sulfoximine Propargyl Carbamates under Improved Conditions for Rhodium Catalyzed Carbamate Transfer to Sulfoxides, The Journal of Organic Chemistry, ISSN: 0022-3263

Sulfoximines provide aza-analogues of sulfones, with potentially improved properties for medicinal chemistry. The sulfoximine nitrogen also provides an additional vector for the inclusion of other functionality. Here, we report improved conditions for rhodium catalyzed synthesis of sulfoximine (and sulfilimine) carbamates, especially for previously low-yielding carbamates containing pi-functionality. Notably we report the preparation of propargyl sulfoximine carbamates to provide an alkyne as a potential click handle. Using Rh2(esp)2 as catalyst and a DOE optimization approach provided considerably increased yields.

Journal article

Qin B, Craven GB, Hou P, Chesti J, Lu X, Child ES, Morgan RML, Niu W, Zhao L, Armstrong A, Mann DJ, Cui Set al., 2022, Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease, ACTA PHARMACEUTICA SINICA B, Vol: 12, Pages: 3924-3933, ISSN: 2211-3835

Journal article

Muhieddine MH, Viswanath SK, Armstrong A, Galindo A, Adjiman CSet al., 2022, Multi-objective optimisation for early-stage pharmaceutical process development, Computer Aided Chemical Engineering, Pages: 2161-2166

The pharmaceutical industry is under constant pressure to deliver its products quickly and effectively while minimising development costs and pursuing green pharmaceutical manufacturing methods. Given the many considerations in process development, a model-based method that takes multiple performance metrics into account is proposed for early process development. Several key performance indicators are identified, namely environmental footprint, cost, and conversion, selectivity, and yield. We employ multi-objective optimisation to assess the trade-offs between capital cost as one objective, and selectivity or conversion as a second objective, while exploring the interdependencies between all performance indicators. The approach is applied to two multiphasic reactions, each occurring in a 6-stage cascade CSTR: the hydrogenation of 4-Isobutylacetophenone (4-IBAP) to 1-(4-Isobutylphenyl) ethanol (4-IBPE) and the carbonylation of 4-IBPE to Ibuprofen (IBP).

Book chapter

Gui L, Armstrong A, Galindo A, Sayyed FB, Kolis SP, Adjiman CSet al., 2022, Computer-aided solvent design for suppressing HCN generation in amino acid activation, Computer Aided Chemical Engineering, Pages: 607-612

A highly toxic compound, hydrogen cyanide (HCN), was discovered to result from the reaction between Ethyl cyano (hydroxyimino) acetate (Oxyma) and diisopropylcarbodiimide (DIC), a popular reagent combination for amino acid activation. The reaction solvent has been found to influence the amount of HCN produced so that judicious solvent choice offers a route to suppressing HCN formation. Given the safety implications and the time-demanding nature of experimental solvent selection, we employ a methodology of quantum mechanical computer-aided molecular design (QM-CAMD) to design a new reaction solvent in order to minimize the amount of HCN formed. In this work, we improve on the original QM-CAMD approach with an enhanced surrogate model to predict the reaction rate constant from several solvent properties. A set of solvents is selected for model regression using model-based design of experiments (MBDoE), where the determinant of the information matrix of the design, known as D-criterion, is maximized. The use of a model-based approach is especially beneficial here as it links the large discrete space of solvent molecules to the reduced space of solvent properties. The resulting surrogate model exhibits an improved adjusted coefficient of determination and leads to more accurate predicted rate constants than the model generated without using MBDoE. The proposed DoE-QM-CAMD algorithm reaches convergence in one iteration. In the future, the main reaction of amino acid activation will be considered to design a solvent that maintains the rate of the main reaction while minimizing HCN generation.

Book chapter

Muhieddine MH, Jonuzaj S, Viswanath SK, Armstrong A, Galindo A, Adjiman CSet al., 2022, Model-based solvent selection for integrated synthesis, crystallisation and isolation processes, Computer Aided Chemical Engineering, Pages: 601-606

We present a systematic process-wide solvent selection tool based on computer-aided mixture/blend design (CAMbD) (Gani, 2004) for the integrated synthesis, crystallisation and isolation of pharmaceutical compounds. The method proposed simultaneously identifies the solvent and/or anti-solvent mixture, mixture composition and process temperatures that optimise one or more key performance indicators. Additionally, the method entails comprehensive design specifications for the integrated process, such as the miscibility of the synthesis, crystallisation and wash solvents. The design approach is illustrated by identifying solvent mixtures for the synthesis, crystallisation and isolation of mefenamic acid. Furthermore, a multi-objective CAMbD problem is formulated and shows that a mefenamic acid with purity of 98.8% can be achieved without significant loss of process performance in terms of the solvent E-factor.

Book chapter

Jamshidiha M, Lanyon-Hogg T, Sutherell C, Craven G, Tersa M, De Vita E, Brustur D, Perez-Doraldo I, Hassan S, Petracca R, Morgan R, Sanz-Hernández M, Norman J, Armstrong A, Mann D, Cota E, Tate Eet al., 2021, Identification of the first structurally validated covalent ligands of the small GTPase RAB27A, RSC Medicinal Chemistry, Vol: 13, Pages: 150-155, ISSN: 2632-8682

Rab27A is a small GTPase, which mediates transport and docking of secretory vesicles at the plasma membrane via protein–protein interactions (PPIs) with effector proteins. Rab27A promotes the growth and invasion of multiple cancer types such as breast, lung and pancreatic, by enhancing secretion of chemokines, metalloproteases and exosomes. The significant role of Rab27A in multiple cancer types and the minor role in adults suggest that Rab27A may be a suitable target to disrupt cancer metastasis. Similar to many GTPases, the flat topology of the Rab27A-effector PPI interface and the high affinity for GTP make it a challenging target for inhibition by small molecules. Reported co-crystal structures show that several effectors of Rab27A interact with the Rab27A SF4 pocket (‘WF-binding pocket’) via a conserved tryptophan–phenylalanine (WF) dipeptide motif. To obtain structural insight into the ligandability of this pocket, a novel construct was designed fusing Rab27A to part of an effector protein (fRab27A), allowing crystallisation of Rab27A in high throughput. The paradigm of KRas covalent inhibitor development highlights the challenge presented by GTPase proteins as targets. However, taking advantage of two cysteine residues, C123 and C188, that flank the WF pocket and are unique to Rab27A and Rab27B among the >60 Rab family proteins, we used the quantitative Irreversible Tethering (qIT) assay to identify the first covalent ligands for native Rab27A. The binding modes of two hits were elucidated by co-crystallisation with fRab27A, exemplifying a platform for identifying suitable lead fragments for future development of competitive inhibitors of the Rab27A-effector interaction interface, corroborating the use of covalent libraries to tackle challenging targets.

Journal article

Martini S, Davis K, Faraway R, Elze L, Lockwood N, Jones A, Xie X, McDonald NQ, Mann DJ, Armstrong A, Ule J, Parker PJet al., 2021, A genetically-encoded crosslinker screen identifies SERBP1 as a PKC epsilon substrate influencing translation and cell division, NATURE COMMUNICATIONS, Vol: 12

Journal article

Diamanti A, Ganase Z, Grant E, Armstrong A, Piccione PM, Rea AM, Richardson J, Galindo A, Adjiman CSet al., 2021, Mechanism, kinetics and selectivity of a Williamson ether synthesis: elucidation under different reaction conditions, REACTION CHEMISTRY & ENGINEERING, Vol: 6, Pages: 1195-+, ISSN: 2058-9883

Journal article

Craven G, Briggs E, Zammit CM, McDermott A, Greed S, Affron D, Leinfellner C, Cudmore HR, Tweedy RR, Luisi R, Bull J, Armstrong Aet al., 2021, Synthesis and configurational assignment of vinyl sulfoximines and sulfonimidamides, Journal of Organic Chemistry, Vol: 86, Pages: 7403-7424, ISSN: 0022-3263

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electro-philic chemical space. We demonstrate how late stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation.

Journal article

Watson L, Soliman TN, Davis K, Kelly J, Lockwood N, Yang X, Lynham S, Scott JD, Crossland V, McDonald NQ, Mann DJ, Armstrong A, Eggert U, Parker PJet al., 2021, Co-ordinated control of the Aurora B abscission checkpoint by PKC epsilon complex assembly, midbody recruitment and retention, BIOCHEMICAL JOURNAL, Vol: 478, Pages: 2247-2263, ISSN: 0264-6021

Journal article

Craven GB, Armstrong A, Mann DJ, 2020, Quantitative Irreversible Tethering (qIT) for Target-directed Covalent Fragment Screening, BIO-PROTOCOL, Vol: 10

Journal article

Qin B, Craven GB, Hou P, Lu X, Child ES, Morgan RML, Armstrong A, Mann DJ, Cui Set al., 2020, Acrylamide Fragment Inhibitors that Induce Unprecedented Conformational Distortions in Enterovirus 71 3C and SARS-CoV-2 Main Protease

<jats:title>ABSTRACT</jats:title><jats:p>RNA viruses are critically dependent upon virally encoded proteases that cleave the viral polyproteins into functional mature proteins. Many of these proteases are structurally conserved with an essential catalytic cysteine and this offers the opportunity to irreversibly inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that selectively target the active site cysteine of the 3C protease (3C<jats:sup>pro</jats:sup>) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we effectively re-purpose these hits towards the main protease (M<jats:sup>pro</jats:sup>) of SARS-CoV-2 which shares the 3C-like fold as well as similar catalytic-triad. We demonstrate that the hit fragments covalently link to the catalytic cysteine of M<jats:sup>pro</jats:sup> to inhibit its activity. In addition, we provide the first demonstration that targeting the active site cysteine of M<jats:sup>pro</jats:sup> can also have profound allosteric effects, distorting secondary structures required for formation of the active dimeric unit of M<jats:sup>pro</jats:sup>. These new data provide novel mechanistic insights into the design of EV71 3C<jats:sup>pro</jats:sup> and SARS-CoV-2 M<jats:sup>pro</jats:sup> inhibitors and identify acrylamide-tagged pharmacophores for elaboration into more selective agents of therapeutic potential.</jats:p>

Journal article

Craven GB, Affron DP, Kösel T, Wong TLM, Jukes ZH, Liu C-T, Morgan RML, Armstrong A, Mann DJet al., 2020, Multiparameter kinetic analysis for covalent fragment optimization using quantitative irreversible tethering (qIT), ChemBioChem: a European journal of chemical biology, Vol: 21, Pages: 3417-3422, ISSN: 1439-4227

Covalent fragments are increasingly being implemented to develop chemical probes but the complex relationship between fragment structure and binding kinetics makes optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing methods for covalent fragment hit identification by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through simultaneous determination of Ki, kinact and intrinsic reactivity. We apply this approach to develop novel probes against electrophile sensitive kinases and showcase how multiparameter kinetic analysis enabled a successful fragment merging strategy.

Journal article

Evans LE, Krishna A, Ma Y, Webb TE, Marshall DC, Tooke CL, Spencer J, Clarke TB, Armstrong A, Edwards Aet al., 2019, Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug., Journal of Medicinal Chemistry, Vol: 62, Pages: 4411-4425, ISSN: 0022-2623

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our pro-drug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

Journal article

Craven G, Affron D, Raymond P, Mann D, Armstrong Aet al., 2019, Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy, MedChemComm, Vol: 10, Pages: 158-163, ISSN: 2040-2503

Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.

Journal article

Craven G, Affron D, Allen C, Matthies S, Greener J, Morgan R, Tate E, Armstrong A, Mann Det al., 2018, High-throughput kinetic analysis for target-directed covalent ligand discovery, Angewandte Chemie International Edition, Vol: 57, Pages: 5257-5261, ISSN: 1433-7851

Cysteine-­reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-­quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-­reactive compounds. Here we describe quantitative irreversible tethering(qIT), a general method for screening cysteine-­reactive small moleculesbased upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-­selective allosteric (type IV) kinase inhibitor whose novel mode-­of-­action could be exploited therapeutically.

Journal article

Craven GB, Affron DP, Allen CE, Matthies S, Greener JG, Morgan RML, Tate EW, Armstrong A, Mann DJet al., 2018, High-throughput kinetic analysis for target-directed covalent ligand discovery, Angewandte Chemie, Vol: 130, Pages: 5355-5359, ISSN: 0044-8249

Cysteine‐reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2‐selective allosteric (type IV) kinase inhibitor whose novel mode‐of‐action could be exploited therapeutically.

Journal article

Mann D, Armstrong A, Craven G, Matthies Set al., 2018, (WO2018033753) ASSAY, PCT/GB2017/052456

The present invention relates to a method of measuring the rate of reaction between a target molecule and a ligand candidate, ligands of interest identified according to this method and drugs developed from such ligands. The present invention also relates to a method of measuring the rate of reaction between a thiol and a molecule capable of reacting with said thiol.

Patent

Grant E, Pan Y, Richardson J, Martinelli JR, Armstrong A, Galindo A, Adjiman CSet al., 2018, Multi-Objective Computer-Aided Solvent Design for Selectivity and Rate in Reactions, Computer Aided Chemical Engineering, Pages: 2437-2442

A hybrid empirical computer-aided methodology to design the solvent for a reaction, incorporating both selectivity and rate, is presented. A small initial set of diverse solvents is used, for which experimental, in situ kinetic data are obtained. A surrogate model is utilized to correlate the reaction kinetics with solvent properties and a computer-aided molecular design (CAMD) multi-objective optimization problem is then formulated to identify solvents with improved performance compared with the initial solvent set. This methodology is applied to an SNAr reaction of 2,4-difluoroacetophenone with pyrrolidine, which demonstrates an interesting effect of solvent on both the selectivity of the ortho-:para-substitution ratio and the overall rate of the reaction. A set of Pareto optimal solutions is identified, highlighting the trade-off between reaction rate and selectivity.

Book chapter

Armstrong A, Ces O, Compte RV, 2017, All aboard for chemistry, CHEMISTRY & INDUSTRY, Vol: 81, Pages: 14-15, ISSN: 0009-3068

Journal article

Sung S, Sale D, Braddock DC, Armstrong A, Brenan C, Davies RPet al., 2016, Mechanistic studies on the copper-catalyzed N-arylation of alkylamines promoted by organic soluble ionic bases, ACS Catalysis, Vol: 6, Pages: 3965-3974, ISSN: 2155-5435

Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, negative first-order kinetics in [TBPM] was observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addition pathway. On the basis of these findings, a more detailed mechanistic cycle for the C–N coupling is proposed, including catalyst deactivation pathways.

Journal article

Byrne B, Alguel Y, Scull NJ, Craven G, Armstrong A, Iwata S, Diallinas G, Amillis S, Capaldi S, Cameron AD, Lambrinidis G, Mikros Eet al., 2016, Structure of eukaryotic purine/Hþ symporter UapA suggests a role for homodimerization in transport activity, Nature Communications, Vol: 7, Pages: 1-9, ISSN: 2041-1723

The uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.

Journal article

Bures Amat J, Blackmond DG, armstrong A, 2016, Explaining Anomalies in Enamine Catalysis: “Downstream Species” as a New Paradigm for Stereocontrol, Accounts of Chemical Research, ISSN: 1520-4898

Journal article

Armstrong A, Pullin RDC, Scutt JN, 2015, Tertiary Amine Promoted Aziridination: Preparation of NH-Aziridines from Aliphatic ,-Unsaturated Ketones, SYNLETT, Vol: 27, Pages: 151-155, ISSN: 0936-5214

trans-NH-Aziridines were prepared from aliphatic α,β-unsaturated ketones using a tertiary amine promoted reaction via in situ generated N,N-ylides. Through use of modified conditions the reaction proved to be applicable for the diastereoselective aziridination of a range of enolisable aliphatic α,β-unsaturated ketones of varying substitution patterns.

Journal article

Sung S, Braddock DC, Armstrong A, Brennan C, Sale D, White AJP, Davies RPet al., 2015, Synthesis, Characterisation and Reactivity of Copper(I) Amide Complexes and Studies on Their Role in the Modified Ullmann Amination Reaction, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 21, Pages: 7179-7192, ISSN: 0947-6539

Journal article

Allen CE, Curran PR, Brearley AS, Boissel V, Sviridenko L, Press NJ, Stonehouse JP, Armstrong Aet al., 2015, Efficient and Facile Synthesis of Acrylamide Libraries for Protein-Guided Tethering, ORGANIC LETTERS, Vol: 17, Pages: 458-460, ISSN: 1523-7060

Journal article

Bures J, Dingwall P, Armstrong A, Blackmond DGet al., 2014, Rationalization of an Unusual Solvent-Induced Inversion of Enantio-meric Excess in Organocatalytic Selenylation of Aldehydes, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 53, Pages: 8700-8704, ISSN: 1433-7851

Journal article

Armstrong A, Emmerson DPG, Milner HJ, Sheppard RJet al., 2014, [2,3]-Sigmatropic Rearrangement of Allylic Selenimides: Strategy for the Synthesis of Peptides, Peptidomimetics, and N-Aryl Vinyl Glycines, JOURNAL OF ORGANIC CHEMISTRY, Vol: 79, Pages: 3895-3907, ISSN: 0022-3263

Journal article

Armstrong A, Pullin RDC, Jenner CR, Foo K, White AJP, Scutt JNet al., 2014, Tertiary amine-promoted enone aziridination: investigations into factors influencing enantioselective induction, TETRAHEDRON-ASYMMETRY, Vol: 25, Pages: 74-86, ISSN: 0957-4166

Journal article

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