Publications
177 results found
Brandt JR, Salerno F, Fuchter MJ, 2017, The added value of small-molecule chirality in technological applications, Nature Reviews Chemistry, Vol: 1, ISSN: 2397-3358
Chirality is a fundamental symmetry property; chiral objects, such as chiral small molecules, exist as a pair of non-superimposable mirror images. Although small-molecule chirality is routinely considered in biologically focused application areas (such as drug discovery and chemical biology), other areas of scientific development have not considered small-molecule chirality to be central to their approach. In this Review, we highlight recent research in which chirality has enabled advancement in technological applications. We showcase examples in which the presence of small-molecule chirality is exploited in ways beyond the simple interaction of two different chiral molecules; this can enable the detection and emission of chiral light, help to control molecular motion, or provide a means to control electron spin and bulk charge transport. Thus, we demonstrate that small-molecule chirality is a highly promising avenue for a wide range of technologically oriented scientific endeavours.
Sundriyal S, Chen P, Lubin A, et al., 2017, Identification of diaminoquinazoline histone lysine methyltransferase structure activity relationships that allow for segregation of human G9a inhibition and anti-Plasmodium activity, MedChemComm, Vol: 8, Pages: 1069-1092, ISSN: 2040-2511
Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites). However, future development of this series will need to address host versus parasite selectivity, where inhibitory activity against human G9a is removed from the lead compounds, while maintaining potent anti-Plasmodium activity. Herein, we report an extensive study of the SAR of this series against both G9a and P. falciparum. We have identified key SAR features which demonstrate that high parasite vs. G9a selectivity can be achieved by selecting appropriate substituents at position 2, 4 and 7 of the quinazoline ring. We have also, in turn, discovered that potent G9a inhibitors can be identified by employing a 6-carbon ‘Nle mimic’ at position 7. Together, this data suggests that while broadly similar, the G9a and potential PfHKMT target(s) binding pockets and/or binding modes of the diaminoquinazoline analogues exhibit clear and exploitable differences. Based on this, we believe this scaffold to have clear potential for development into a novel anti-malarial therapeutic.
Sundriyal S, Moniot S, Mahmud Z, et al., 2017, Thienopyrimidinone based sirtuin-2 (SIRT2)-selective inhibitors bind in the ligand induced 'selectivity pocket'., Journal of Medicinal Chemistry, Vol: 60, Pages: 1928-1945, ISSN: 0022-2623
Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a co-crystal structure of one of our compounds (29c) bound to SIRT2. This reveals our series to induce the formation of a previously reported 'selectivity pocket', but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors.
Hazel P, Kroll SH, Bondke A, et al., 2017, Inhibitor selectivity for cyclin-dependent kinase 7: a structural, thermodynamic, and modelling study, Chemmedchem, Vol: 12, Pages: 372-380, ISSN: 1860-7187
Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.
Calbo J, Weston CE, White A, et al., 2016, Tuning azoheteroarene photoswitch performance through heteroaryl design, Journal of the American Chemical Society, Vol: 139, Pages: 1261-1274, ISSN: 1520-5126
Photoswitchable compounds, which can be reversibly switched between two isomers by light, continue to attract significant attention for a wide array of applications. Azoheteroarenes represent a relatively new but understudied type of photoswitch, where one of the aryl rings from the conventional azobenzene class has been replaced with a five-membered heteroaromatic ring. Initial studies have suggested the azoheteroarenes - the arylazopyrazoles in particular - to have excellent photoswitching properties (quantitative switching and long Z isomer half-life). Here we present a systematic computational and experimental study to elucidate the origin of the long thermal half-lives and excellent addressability of the arylazopyrazoles, and apply this understanding to determine important structure-property relationships for a wide array of comparable azoheteroaryl photoswitches. We identify compounds with Z isomer half-lives ranging from seconds to hours, to days and to years, and variable absorption characteristics; all through tuning of the heteraromatic ring. Conformation perhaps plays the largest role in determining such properties; where the compounds with the longest isomerization half-lives adopt a T-shaped ground state Z isomer conformation and proceed through a T-shaped isomerization pathway, whereas the most complete photoswitching is achieved for compounds that have a twisted (rather than T-shaped) Z-isomer conformation. By balancing these factors, we report a new azopyrazole 3pzH, which can be quantitatively switched to its Z-isomer (>98%) with 355 nm irradiation, near-quantitatively (97%) switched back to the E isomer with 532 nm irradiation, and has a very long half-life for thermal isomerisation (t1/2 = 74 d at 25 °C). Given the large tunability of their properties, the predictive nature of their performance, and the other functional opportunities afforded by usage of a heteroaromatic system, we believe the azoheteroaryl photoswitches to have huge potent
Scott DJ, Phillips NA, Sapsford JS, et al., 2016, Versatile Catalytic Hydrogenation Using A Simple SnIV Lewis Acid, Angewandte Chemie International Edition, Vol: 55, Pages: 14738-14742, ISSN: 1433-7851
Despite the rapid development of frustrated Lewis pair (FLP) chemistry over the last ten years, its application in catalytic hydrogenations remains dependent on a narrow family of structurally similar early main-group Lewis acids (LAs), inevitably placing limitations on reactivity, sensitivity and substrate scope. Herein we describe the FLP-mediated H2 activation and catalytic hydrogenation activity of the alternative LA iPr3SnOTf, which acts as a surrogate for the trialkylstannylium ion iPr3Sn+, and is rapidly and easily prepared from simple, inexpensive starting materials. This highly thermally robust LA is found to be competent in the hydrogenation of a number of different unsaturated functional groups (which is unique to date for main-group FLP LAs not based on boron), and also displays a remarkable tolerance to moisture.
Weston CE, Kraemer A, Colin F, et al., 2016, Towards photopharmacological antimicrobial chemotherapy using photoswitchable amidohydrolase inhibitors, ACS Infectious Diseases, Vol: 3, Pages: 152-161, ISSN: 2373-8227
Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitch embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles. While both classes of inhibitor show excellent inhibitory activity (nM IC50 values) of the target enzymes and promising differential activity of the switchable E- and Z-isomeric forms, the arylazopyrazoles exhibit better intrinsic photoswitch performance (more complete switching, longer thermal lifetime of the Z‑isomer). We also report protein-ligand crystal structures of the E-isomers of both an azobenzene and an arylazopyrazole inhibitor, bound to bacterial histone deacetylase-like amidohydrolases (HDAHs). These structures not only uncover interactions important for inhibitor binding, but also reveal conformational differences between the two photoswitch inhibitor classes. As such, our data may pave the way for the design of improved photopharmacological agents targeting the HDAC superfamily.
Ali S, Patel H, Periyasamy M, et al., 2016, ICEC0942, an orally bioavailable selective inhibitor of CDK7 for breast cancer, UK Breast Cancer Research Symposium, Publisher: Springer Verlag, Pages: 195-195, ISSN: 0167-6806
Weston CE, Richardson RD, Haycock PR, et al., 2016, Correction to "Arylazopyrazoles: Azoheteroarene Photoswitches Offering Quantitative Isomerization and Long Thermal Half-Lives., Journal of the American Chemical Society, Vol: 138, Pages: 10716-10716, ISSN: 1520-5126
Brandt JR, Wang X, Yang Y, et al., 2016, Circularly polarized phosphorescent electroluminescence with a high dissymmetry factor from PHOLEDs based on a platinahelicene, Journal of the American Chemical Society, Vol: 138, Pages: 9743-9746, ISSN: 1520-5126
Circularly polarized (CP) light is of interest inareas such as quantum optical computing, optical spintronics,biomedicine and high efficiency displays. Direct emissionof CP light from organic light-emitting diodes (OLEDs) hasbeen a focus of research as it has the immediate applicationof increasing efficiency and simplifying device architecture inOLED based displays. High dissymmetry (gEL) factor valueshave been reported for devices employing fluorescent polymers,but these CP-OLEDs are limited in their ultimate efficienciesby the type of emissive electronic transitions involved.In contrast, phosphorescent OLEDs (PHOLEDs) canemit light from triplet excited states and can thereforeachieve very high efficiencies. However, CP-PHOLEDs aresignificantly understudied and the two previous reports sufferedfrom very low brightness or gEL values. Here, we use aplatinahelicene complex to construct a CP-PHOLED thatachieves both a display level brightness and a high gEL factor.The dissymmetry of CP emission reached with this proof-ofconceptsingle-layer helicene-based device is sufficient toprovide real-world benefits over non-polarized emission, andpaves the way towards chiral metal complex–based CPPHOLEDdisplays.
Davidson RWM, Fuchter MJ, 2016, Direct NHC-catalysed redox amidation using CO2 for traceless masking of amine nucleophiles, Chemical Communications, Vol: 52, Pages: 11638-11641, ISSN: 1364-548X
The N-heterocyclic carbene (NHC)-catalysed redox amidation reaction is poorly developed and usually requires catalytic co-additives for electron-rich amine nucleophiles. We report a masking strategy (using CO2) that couples release of the free amine nucleophile to catalytic turnover, and in doing so, enables direct catalytic redox amidation of electron-rich amines.
Fuchter MJ, Weston CE, Richardson RD, 2016, Photoswitchable basicity through the use of azoheteroarenes, Chemical Communications, Vol: 52, Pages: 4521-4524, ISSN: 1364-548X
Azoheteroarene photoswitches offer functional advantages over their more conventional azobenzene counterparts by virtue of their heteroaromatic ring(s). Here we report that azobis(2-imidazole) functions as a photoswitchable base due to the additional proton stabilisation that is possible in the protonated Z isomer, facilitated by the basic imidazole nitrogens. This thermodynamic difference in stability corresponds to a 1.3 unit difference in pKa values between the E and Z isomers. This pKa difference can be used to reversibly control solution pH.
Chen PB, Ding S, Zanghì G, et al., 2016, Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites., Scientific Reports, Vol: 6, ISSN: 2045-2322
Epigenetic control via reversible histone methylation regulates transcriptional activation throughout the malaria parasite genome, controls the repression of multi-copy virulence gene families and determines sexual stage commitment. Plasmodium falciparum encodes ten predicted SET domain-containing protein methyltransferases, six of which have been shown to be refractory to knock-out in blood stage parasites. We have expressed and purified the first recombinant malaria methyltransferase in sufficient quantities to perform a full enzymatic characterization and reveal the ill-defined PfSET7 is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines 4 and 9. Steady-state kinetics of the PfSET7 enzyme are similar to previously characterized histone methyltransferase enzymes from other organisms, however, PfSET7 displays specific protein substrate preference towards nucleosomes with pre-existing histone H3 lysine 14 acetylation. Interestingly, PfSET7 localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stage parasites, and throughout the cytoplasm in salivary gland sporozoites. Characterized recombinant PfSET7 now allows for target based inhibitor discovery. Specific PfSET7 inhibitors can aid in further investigating the biological role of this specific methyltransferase in transmission, hepatic and blood stage parasites, and may ultimately lead to the development of suitable antimalarial drug candidates against this novel class of essential parasite enzymes.
Fuchter MJ, 2015, Young Career Focus: Dr. Matthew J. Fuchter (Imperial College London, UK), SYNTHESIS-STUTTGART, Vol: 47, Pages: A152-A155, ISSN: 0039-7881
Curry E, Green I, Chapman-Rothe N, et al., 2015, Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, Clinical Epigenetics, Vol: 7, ISSN: 1868-7083
Background: Many cancers show aberrant silencing of gene expression andoverexpression of histone methyltransferases. The histone methyltransferases (HKMT)EZH2 and EHMT2 maintain the repressive chromatin histone marks H3K27 and H3K9methylation respectively, which are associated with transcriptional silencing. Althoughselective HKMT inhibitors reduce levels of individual repressive marks, removal ofH3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducingexpression of genes with multiple repressive marks.Results: We report that gene expression and inhibition of triple negative breast cancer cellgrowth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2,either by siRNA knockdown or pharmacological inhibition, rather than independently. Indeed,expression of certain genes is only induced upon dual inhibition. We sought to identifycompounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-basedassay, based on the substrate-competitive EHMT2 inhibitor BIX01294, we have identifiedproof-of-concept compounds that induce re-expression of a subset of genes consistent withdual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marksand an increase in permissive marks at the promoter and transcription start site of reexpressedgenes, while Western analysis showed reduction in global levels of H3K27me3and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma celllines with low to sub-micromolar IC50s. Biochemically, the compounds are substratecompetitive inhibitors against both EZH2 and EHMT1/2.Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is moreeffective at eliciting biological responses of gene transcription and cancer cell growthinhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.
Scott DJ, Simmons TR, Lawrence EJ, et al., 2015, Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation, ACS Catalysis, Vol: 5, Pages: 5540-5544, ISSN: 2155-5435
Despite rapid advances in the field of metal-free, “frustrated Lewis pair” (FLP)-catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants.
Bultinck P, Cherblanc FL, Fuchter MJ, et al., 2015, Chiroptical Studies on Brevianamide B: Vibrational and Electronic Circular Dichroism Confronted, JOURNAL OF ORGANIC CHEMISTRY, Vol: 80, Pages: 3359-3367, ISSN: 0022-3263
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- Citations: 6
Anwar A, Archibald S, Audisio D, et al., 2015, Abstracts., J Labelled Comp Radiopharm, Vol: 58, Pages: 147-155
Fuchter MJ, 2015, Carbon-14 reprocessing at cardiff, Publisher: WILEY-BLACKWELL, Pages: 149-150, ISSN: 0362-4803
Malmquist NA, Sundriyal S, Caron J, et al., 2015, Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 59, Pages: 950-959, ISSN: 0066-4804
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- Citations: 37
Di Fruscia P, Zacharioudakis E, Liu C, et al., 2015, The Discovery of a Highly Selective 5,6,7,8-Tetrahydrobenzo[4,5]thieno[ 2,3-<i>d</i>] pyrimidin-4(3<i>H</i>)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson's Disease Model, CHEMMEDCHEM, Vol: 10, Pages: 69-82, ISSN: 1860-7179
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- Citations: 58
Richardson RD, Baud MGJ, Weston CE, et al., 2015, Dual wavelength asymmetric photochemical synthesis with circularly polarized light, Chemical Science, Vol: 6, Pages: 3853-3862, ISSN: 2041-6539
Udemba A, Smith G, Nguyen Q-D, et al., 2015, Design, synthesis and initial characterisation of a radiolabelled [<SUP>18</SUP>F]pyrimidoindolone probe for detecting activated caspase-3/7, ORGANIC & BIOMOLECULAR CHEMISTRY, Vol: 13, Pages: 5418-5423, ISSN: 1477-0520
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- Citations: 7
Scott DJ, Fuchter MJ, Ashley AE, 2014, Nonmetal catalyzed hydrogenation of carbonyl compounds, Journal of the American Chemical Society, Vol: 136, Pages: 15813-15816, ISSN: 0002-7863
Solutions of the Lewis acid B(C6F5)3 in 1,4-dioxane are found to effectively catalyze the hydrogenation of a variety of ketones and aldehydes. These reactions, the first to allow entirely metal-free catalytic hydrogenation of carbonyl groups under relatively mild reaction conditions, are found to proceed via a “frustrated Lewis pair” mechanism in which the solvent, a weak Brønsted base yet moderately strong donor, plays a pivotal role.
Forkel NV, Henderson DA, Fuchter MJ, 2014, Calcium-mediated stereoselective reduction of α,β-epoxy ketones, TETRAHEDRON LETTERS, Vol: 55, Pages: 5511-5514, ISSN: 0040-4039
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- Citations: 10
Sundriyal S, Malmquist NA, Caron J, et al., 2014, Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-Stage Antimalarial Compounds, CHEMMEDCHEM, Vol: 9, Pages: 2360-2373, ISSN: 1860-7179
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- Citations: 27
Scott DJ, Fuchter MJ, Ashley AE, 2014, Metal-free hydrogenation catalyzed by an air-stable borane: use of solvent as a frustrated Lewis base, Angewandte Chemie International Edition, Vol: 53, Pages: 10218-10222, ISSN: 1433-7851
In recent years ‘frustrated Lewis pairs’ (FLPs) have been shown to be effective metal‐free catalysts for the hydrogenation of many unsaturated substrates. Even so, limited functional‐group tolerance restricts the range of solvents in which FLP‐mediated reactions can be performed, with all FLP‐mediated hydrogenations reported to date carried out in non‐donor hydrocarbon or chlorinated solvents. Herein we report that the bulky Lewis acids B(C6Cl5)x(C6F5)3−x (x=0–3) are capable of heterolytic H2 activation in the strong‐donor solvent THF, in the absence of any additional Lewis base. This allows metal‐free catalytic hydrogenations to be performed in donor solvent media under mild conditions; these systems are particularly effective for the hydrogenation of weakly basic substrates, including the first examples of metal‐free catalytic hydrogenation of furan heterocycles. The air‐stability of the most effective borane, B(C6Cl5)(C6F5)2, makes this a practically simple reaction method.
Meyners C, Baud MGJ, Fuchter MJ, et al., 2014, Kinetic method for the large-scale analysis of the binding mechanism of histone deacetylase inhibitors, ANALYTICAL BIOCHEMISTRY, Vol: 460, Pages: 39-46, ISSN: 0003-2697
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- Citations: 14
Weston CE, Richardson RD, Haycock PR, et al., 2014, Arylazopyrazoles: azoheteroarene photoswitches offering quantitative isomerization and long thermal half-lives, Journal of the American Chemical Society, Vol: 136, Pages: 11878-11881, ISSN: 0002-7863
Arylazopyrazoles, a novel class of five-membered azo photoswitches, offer quantitative photoswitching and high thermal stability of the Z isomer (half-lives of 10 and ∼1000 days). The conformation of the Z isomers of these compounds, and also the arylazopyrroles, is highly dependent on the substitution pattern on the heteroarene, allowing a twisted or planar geometry, which in turn has a significant impact on the electronic spectral properties of the compounds.
Dembele L, Franetich J-F, Lorthiois A, et al., 2014, Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures, Nature Medicine, Vol: 20, Pages: 307-312, ISSN: 1078-8956
Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi–infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.
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