Co-reporter:Emily Knight, Eifion Robinson, Natalia Smoktunowicz, Rachel C. Chambers, Abil E. Aliev, Graham G. Inglis, Vijay Chudasama and Stephen Caddick
Organic & Biomolecular Chemistry 2016 vol. 14(Issue 12) pp:3264-3274
Publication Date(Web):24 Feb 2016
DOI:10.1039/C5OB02541A
Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM.
Co-reporter:Eifion Robinson, Emily Knight, Natalia Smoktunowicz, Rachel C. Chambers, Graham G. Inglis, Vijay Chudasama and Stephen Caddick
Organic & Biomolecular Chemistry 2016 vol. 14(Issue 12) pp:3198-3201
Publication Date(Web):25 Feb 2016
DOI:10.1039/C6OB00332J
The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259.
Co-reporter:Felix F. Schumacher, João P. M. Nunes, Antoine Maruani, Vijay Chudasama, Mark E. B. Smith, Kerry A. Chester, James R. Baker and Stephen Caddick
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 37) pp:7261-7269
Publication Date(Web):07 Aug 2014
DOI:10.1039/C4OB01550A
The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody–drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody.
Co-reporter:João P. M. Nunes, Carlos A. M. Afonso and Stephen Caddick
RSC Advances 2013 vol. 3(Issue 35) pp:14975-14978
Publication Date(Web):26 Jun 2013
DOI:10.1039/C3RA42663G
Herein we report a new approach to the synthesis of 2,4-bifunctionalised cyclopentenones via one-pot conversion of 2-furaldehyde with morpholine followed by concomitant 1,4 addition and elimination. This protocol has also been extended to afford 2-hydroxy, 2-amino and 2-phenyl cyclopentenones.
Co-reporter:Lourdes Castañeda, Zoë V.F. Wright, Cristina Marculescu, Trang M. Tran, Vijay Chudasama, Antoine Maruani, Elizabeth A. Hull, João P.M. Nunes, Richard J. Fitzmaurice, Mark E.B. Smith, Lyn H. Jones, Stephen Caddick, James R. Baker
Tetrahedron Letters 2013 Volume 54(Issue 27) pp:3493-3495
Publication Date(Web):3 July 2013
DOI:10.1016/j.tetlet.2013.04.088
Bromomaleimides are useful building blocks in synthesis and powerful reagents for the selective chemical modification of proteins. A mild new synthesis of these reagents is described, along with the convenient transferability of the approach to dithiomaleimides and bromopyridazinediones.Figure optionsDownload full-size imageDownload as PowerPoint slide
Co-reporter:Paul Moody;Dr. Mark. E. B. Smith;Dr. Chris P. Ryan;Dr. Vijay Chudasama;Dr. James R. Baker;Dr. Justin Molloy; Stephen Caddick
ChemBioChem 2012 Volume 13( Issue 1) pp:
Publication Date(Web):
DOI:10.1002/cbic.201190090
Co-reporter:Paul Moody;Dr. Mark. E. B. Smith;Dr. Chris P. Ryan;Dr. Vijay Chudasama;Dr. James R. Baker;Dr. Justin Molloy; Stephen Caddick
ChemBioChem 2012 Volume 13( Issue 1) pp:39-41
Publication Date(Web):
DOI:10.1002/cbic.201100603
Co-reporter:Vijay Chudasama, Mark E. B. Smith, Felix F. Schumacher, Danai Papaioannou, Gabriel Waksman, James R. Baker and Stephen Caddick
Chemical Communications 2011 vol. 47(Issue 31) pp:8781-8783
Publication Date(Web):07 Jul 2011
DOI:10.1039/C1CC12807H
Bromopyridazinedione-mediated bioconjugation to a cysteine containing protein and a disulfide containing peptide is described. The conjugates are cleavable in an excess of thiol, including cytoplasmically-relevant concentrations of glutathione, and show a high level of hydrolytic stability. The constructs have the potential for four points of chemical attachment.
Co-reporter:Chris P. Ryan, Mark E. B. Smith, Felix F. Schumacher, Dina Grohmann, Danai Papaioannou, Gabriel Waksman, Finn Werner, James R. Baker and Stephen Caddick
Chemical Communications 2011 vol. 47(Issue 19) pp:5452-5454
Publication Date(Web):05 Apr 2011
DOI:10.1039/C1CC11114K
Controlling maleimide hydrolysis allows the modular construction of bromomaleimide-mediated bioconjugates which are either stable or cleavable in an aqueous, thiol-mediated reducing environment. The application of this methodology to reversible protein biotinylation, the irreversible labeling of peptide disulfide bonds and the assembly of stable, fluorescein-labelled glycoprotein mimics is described.
Co-reporter:Vijay Chudasama, Jenna M. Ahern, Richard J. Fitzmaurice, Stephen Caddick
Tetrahedron Letters 2011 Volume 52(Issue 10) pp:1067-1069
Publication Date(Web):9 March 2011
DOI:10.1016/j.tetlet.2010.12.083
γ-Ketophosphonates are commonly employed as non-hydrolysable phosphate mimetics and as tools in synthesis. The synthesis of γ-ketophosphonates under mild conditions via interception of acyl radicals generated by aldehyde auto-oxidation is described.
Co-reporter:Mark E. B. Smith ; Felix F. Schumacher ; Chris P. Ryan ; Lauren M. Tedaldi ; Danai Papaioannou ; Gabriel Waksman ; Stephen Caddick ;James R. Baker
Journal of the American Chemical Society 2010 Volume 132(Issue 6) pp:1960-1965
Publication Date(Web):January 21, 2010
DOI:10.1021/ja908610s
The maleimide motif is widely used for the selective chemical modification of cysteine residues in proteins. Despite widespread utilization, there are some potential limitations, including the irreversible nature of the reaction and, hence, the modification and the number of attachment positions. We conceived of a new class of maleimide which would address some of these limitations and provide new opportunities for protein modification. We report herein the use of mono- and dibromomaleimides for reversible cysteine modification and illustrate this on the SH2 domain of the Grb2 adaptor protein (L111C). After initial modification of a protein with a bromo- or dibromomaleimide, it is possible to add an equivalent of a second thiol to give further bioconjugation, demonstrating that bromomaleimides offer opportunities for up to three points of attachment. The resultant protein−maleimide products can be cleaved to regenerate the unmodified protein by addition of a phosphine or a large excess of a thiol. Furthermore, dibromomaleimide can insert into a disulfide bond, forming a maleimide bridge, and this is illustrated on the peptide hormone somatostatin. Fluorescein-labeled dibromomaleimide is synthesized and inserted into the disulfide to construct a fluorescent somatostatin analogue. These results highlight the significant potential for this new class of reagents in protein modification.
Co-reporter:Vijay Chudasama, Richard J. Fitzmaurice, Jenna M. Ahern and Stephen Caddick
Chemical Communications 2010 vol. 46(Issue 1) pp:133-135
Publication Date(Web):13 Nov 2009
DOI:10.1039/B914563J
Herein we report a mild, facile method for the preparation of 1,4-keto-sulfonates and sulfones on water. Further synthetic manipulations can result in products that are not readily accessed by hydroacylation of electron rich alkenes.
Co-reporter:Belinda Loh;Luciano Vozzolo;B. James Mok;Chien Chi Lee;Richard J. Fitzmaurice;Ariberto Fassati
Chemical Biology & Drug Design 2010 Volume 75( Issue 5) pp:461-474
Publication Date(Web):
DOI:10.1111/j.1747-0285.2010.00956.x
Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.
Co-reporter:Richard J. Fitzmaurice, Jenna M. Ahern and Stephen Caddick
Organic & Biomolecular Chemistry 2009 vol. 7(Issue 2) pp:235-237
Publication Date(Web):26 Nov 2008
DOI:10.1039/B819235A
A new and simple protocol for the direct functionalisation of aldehydes with concomitant conversion into ketones via C–C bond formation has been developed. The reaction effectively enables the direct C–H activation of an aldehyde by mixing of an aldehyde and a vinyl sulfonate under aerobic conditions or using hydrogen peroxide as a sub-stoichiometric reagent.
Co-reporter:Alexandra K. de K. Lewis, Stephen Caddick, Oriana Esposito, F. Geoffrey N. Cloke and Peter B. Hitchcock
Dalton Transactions 2009 (Issue 35) pp:7094-7098
Publication Date(Web):21 Jul 2009
DOI:10.1039/B907102D
The reaction between 2-chlorobenzylamine or 2-chlorobenzylalcohol and Pd(ItBu)2 (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) in benzene affords the dimeric complexes [Pd(ItBu)(μ-NH{2-CH2C6H4})]2 and [Pd(ItBu)(μ-O{2-CH2C6H4})]2; the latter has been structurally characterised. The syntheses, structural characterisation and reactivity of the Pd-NHC amine complexes [(ItBu)Pd(R-4-C6H4)(morpholine)Cl] (R = Me, OMe, CO2Me), intermediates in the Buchwald–Hartwig aryl amination reaction, are also reported.
Co-reporter:Stephen Caddick, Richard Fitzmaurice
Tetrahedron 2009 65(17) pp: 3325-3355
Publication Date(Web):
DOI:10.1016/j.tet.2009.01.105
Co-reporter:Mark J. Cawley, F. Geoffrey N. Cloke, Richard J. Fitzmaurice, Stuart E. Pearson, James S. Scott and Stephen Caddick
Organic & Biomolecular Chemistry 2008 vol. 6(Issue 15) pp:2820-2825
Publication Date(Web):06 Jun 2008
DOI:10.1039/B801479E
Continuing efforts to establish a more general “user-friendly” protocol for the palladium-catalysed arylation of amines (Buchwald–Hartwig reaction) are described herein. Significant advances have been made through the use of the versatile (SIPr)Pd(methallyl)Cl complex in conjunction with the reliable base lithium hexamethyldisilazide (LHMDS).
Co-reporter:Oriana Esposito, Pedro M. P. Gois, Alexandra K. de K. Lewis, Stephen Caddick, F. Geoffrey N. Cloke and Peter B. Hitchcock
Organometallics 2008 Volume 27(Issue 24) pp:6411-6418
Publication Date(Web):November 13, 2008
DOI:10.1021/om800455h
The dimers [trans-[(neopentyl)Pd(μ-Cl)(ItBu)]2, 2, and (cis-[(neopentyl)Pd(μ-Cl)(IPr)]2, 3 (ItBu = 1,3-bis-tert-butylimidazol-2-ylidene, IPr = 1,3-bis-2,6-diidopropylimidazol-2-ylidene), have been synthesized from [Pd(neopentyl)(Cl)(1,5-COD)], and their reactivity toward a variety of nucleophiles has been evaluated. In particular, this study revealed that 2 can be readily cleaved by primary and secondary amines, affording stable transamination products, which are surprisingly resistant to deprotonation. Dimer 3 was subsequently used as a catalyst in a series of Buchwald−Hartwig amination reactions of aryl chlorides.
Co-reporter:Oriana Esposito, Alexandra K. de K. Lewis, Peter B. Hitchcock, Stephen Caddick and F. Geoffrey N. Cloke
Chemical Communications 2007 (Issue 11) pp:1157-1159
Publication Date(Web):14 Feb 2007
DOI:10.1039/B700671C
The transamination of alkylpalladium halide N-heterocyclic carbene complexes has enabled the isolation of products that reveal interesting insights into the factors which might be barriers to the development of a palladium-catalysed alkyl–amination reaction.
Co-reporter:Jonathan D. Wilden, Lynsey Geldeard, Chieh C. Lee, Duncan B. Judd and Stephen Caddick
Chemical Communications 2007 (Issue 10) pp:1074-1076
Publication Date(Web):21 Dec 2006
DOI:10.1039/B614604J
2,4,6-Trichlorophenol (TCP) sulfonate esters undergo effective aminolysis under conventional heating and microwave irradiation; the reactivity of these species is such that chemoselective transformations of PFP sulfonate esters can be achieved.
Co-reporter:Olivier Thominet, James R. Baker, Hugh Britton, Zac C. Etheridge, Marco G. Soscia and Stephen Caddick
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 22) pp:3703-3712
Publication Date(Web):03 Oct 2007
DOI:10.1039/B711196G
We present herein our recent efforts towards the synthesis of epoxydiynes which represent an unusual structural feature of the neocarzinostatin chromophore. A number of different routes to these epoxydiynes have been explored with varying success. Ultimately a concise and convergent approach was developed, which involved the addition of an allenyl zinc bromide to propargylic ketones/aldehydes followed by epoxide formation. This new protocol enabled us to synthesise a fully elaborated epoxydiyne which will find application for our studies towards the total synthesis of the NCS chromophore.
Co-reporter:Thomas Morris, David Sandham and Stephen Caddick
Organic & Biomolecular Chemistry 2007 vol. 5(Issue 7) pp:1025-1027
Publication Date(Web):05 Feb 2007
DOI:10.1039/B700804J
Functionalization of amino acid C- and N-termini with appropriate olefinic moieties allows for the generation of a peptidomimetic via a stereoselective cross-metathesis.
Co-reporter:James R. Baker Dr.;Derek N. Woolfson ;Frederick W. Muskett Dr.;Rhys G. Stoneman;Michael D. Urbaniak Dr.
ChemBioChem 2007 Volume 8(Issue 7) pp:
Publication Date(Web):24 APR 2007
DOI:10.1002/cbic.200600534
The enediyne chromoproteins are a class of potent antitumour antibiotics comprising a 1:1 complex of a protein and a noncovalently bound chromophore. The protein is required to protect and transport the highly labile chromophore, which acts as the cytotoxic component by reacting with DNA leading to strand cleavage. A derivative of the best-studied member of this class, neocarzinostatin (NCS), is currently in use as a chemotherapeutic in Japan. The application of the chromoproteins as therapeutics along with their unique mode of action has prompted widespread interest in this area. Notable developments include the discovery of non-natural ligands for the apoproteins and the observation that multiple binding modes are available for these ligands in the binding site. Mutation studies on the apoproteins have revealed much about their stability and variability, and the application of an in vitro evolution method has conferred new binding specificity for unrelated ligands. These investigations hold great promise for the application of the apoproteins for drug-delivery, transport and stabilisation systems.
Co-reporter:Richard J. Fitzmaurice, Zac C. Etheridge, Emelie Jumel, Derek N. Woolfson and Stephen Caddick
Chemical Communications 2006 (Issue 46) pp:4814-4816
Publication Date(Web):29 Sep 2006
DOI:10.1039/B610734F
Microwave enhanced diversity-oriented synthesis (MEDOS) using palladium catalysed protocols is introduced as a powerful new strategy for the synthesis of systematically modified small molecules and is highlighted by application to functionalised flavones.
Co-reporter:Patrick Vallance, Hannah D. Bush, B. James Mok, Ramon Hurtado-Guerrero, Herpreet Gill, Sharon Rossiter, Jonathan D. Wilden and Stephen Caddick
Chemical Communications 2005 (Issue 44) pp:5563-5565
Publication Date(Web):11 Oct 2005
DOI:10.1039/B510709A
A range of pentafluorophenyl (PFP) sulfonate esters derived from the reaction of PFP vinyl sulfonate and various nitrones are shown to have significant inhibitory activity against the bacterial enzymes DDAH and ADI.
Co-reporter:Stephen Caddick, Jonathan D. Wilden and Duncan B. Judd
Chemical Communications 2005 (Issue 21) pp:2727-2728
Publication Date(Web):15 Apr 2005
DOI:10.1039/B501212K
Studies on displacement reactions of alkyl pentafluorophenyl (PFP) sulfonates with amines are consistent with a mechanism involving an elimination-addition pathway; comparisons between the reactivity of PFP-sulfonates with sulfonyl chlorides and PFP-sulfonates with PFP-esters are also presented.
Co-reporter:N. R. Treweeke, P. B. Hitchcock, D. A. Pardoe and S. Caddick
Chemical Communications 2005 (Issue 14) pp:1868-1870
Publication Date(Web):08 Feb 2005
DOI:10.1039/B417954D
Diastereoselective substitution reactions of α-bromoacyl-imidazolidinones with nitrogen nucleophiles can be promoted with either retention or inversion of configuration by carrying out reactions under epimerising or non-epimerising conditions.
Co-reporter:Israel Conesa Lerma, Mark J. Cawley, F. Geoffrey N. Cloke, Katherine Arentsen, James S. Scott, Stuart E. Pearson, John Hayler, Stephen Caddick
Journal of Organometallic Chemistry 2005 Volume 690(24–25) pp:5841-5848
Publication Date(Web):1 December 2005
DOI:10.1016/j.jorganchem.2005.07.084
The reactions of a range of secondary amines with aryl bromides and iodides have been performed using an in situ protocol involving palladium and imidazolium salts. Many of these reactions proceed at room temperature, providing a mild protocol for aminations of aryl iodides and bromides. Key to the success of this procedure is the use of lithium hexamethyldisilazide (LHMDS) as base.The reactions of a range of secondary amines with aryl bromides and iodides have been performed using an in situ protocol involving palladium and imidazolium salts. Many of these reactions proceed at room temperature, providing a mild protocol for aminations of aryl iodides and bromides. Key to the success of this procedure is the use of lithium hexamethyldisilazide (LHMDS) as base.
Co-reporter:Stephen Caddick Dr.;F. Geoffrey N. Cloke Dr.;Peter B. Hitchcock Dr.;Alexra K. de K. Lewis
Angewandte Chemie 2004 Volume 116(Issue 43) pp:
Publication Date(Web):2 NOV 2004
DOI:10.1002/ange.200460955
Reaktion wie geschmiert? Bei der Umsetzung von [Ni(1,5-cod)2] (cod=Cyclooctadien) mit 1,3-Bis-tert-butylimidazol-2-yliden entsteht in Gegenwart von Siliconfett das Siloxan-verbrückte Dimer [{Ni[C(NtBuCH)2][O(Me2SiOSiMe2)-μ-O]}2]. In einer fettfreien Apparatur liefert die gleiche Reaktion über zwei strukturell charakterisierte Zwischenstufen das Dimer 1 (siehe Struktur).
Co-reporter:Stephen Caddick Dr.;F. Geoffrey N. Cloke Dr.;Peter B. Hitchcock Dr.;Alexra K. de K. Lewis
Angewandte Chemie International Edition 2004 Volume 43(Issue 43) pp:
Publication Date(Web):2 NOV 2004
DOI:10.1002/anie.200460955
Reaction lubrication? The reaction between [Ni(1,5-cod)2] (cod=cyclooctadiene) and 1,3-bis-tert-butylimidazol-2-ylidene in the presence of silicone grease affords the siloxane bridged dimer [{Ni[C(NtBuCH)2][O(Me2SiOSiMe2)-μ-O]}2]. In a greaseless apparatus, the same reaction yields the dimer 1 (see structure), via two structurally characterized intermediates.
Co-reporter:Oriana Esposito, Alexandra K. de K. Lewis, Peter B. Hitchcock, Stephen Caddick and F. Geoffrey N. Cloke
Chemical Communications 2007(Issue 11) pp:NaN1159-1159
Publication Date(Web):2007/02/14
DOI:10.1039/B700671C
The transamination of alkylpalladium halide N-heterocyclic carbene complexes has enabled the isolation of products that reveal interesting insights into the factors which might be barriers to the development of a palladium-catalysed alkyl–amination reaction.
Co-reporter:Eifion Robinson, Emily Knight, Natalia Smoktunowicz, Rachel C. Chambers, Graham G. Inglis, Vijay Chudasama and Stephen Caddick
Organic & Biomolecular Chemistry 2016 - vol. 14(Issue 12) pp:NaN3201-3201
Publication Date(Web):2016/02/25
DOI:10.1039/C6OB00332J
The discontinuation of PAR-1 antagonist RWJ-58259 beyond use as a biological probe is most likely due to it's short half-life in vivo. However, retention of significant in vivo activity beyond the point where most of the RWJ-58259 had been consumed implies the generation of an active metabolite. Herein we describe the biological activity of a predicted metabolite of RWJ-58259 and the synthesis of analogues designed to enhance the metabolic stability of RWJ-58259.
Co-reporter:Vijay Chudasama, Mark E. B. Smith, Felix F. Schumacher, Danai Papaioannou, Gabriel Waksman, James R. Baker and Stephen Caddick
Chemical Communications 2011 - vol. 47(Issue 31) pp:NaN8783-8783
Publication Date(Web):2011/07/07
DOI:10.1039/C1CC12807H
Bromopyridazinedione-mediated bioconjugation to a cysteine containing protein and a disulfide containing peptide is described. The conjugates are cleavable in an excess of thiol, including cytoplasmically-relevant concentrations of glutathione, and show a high level of hydrolytic stability. The constructs have the potential for four points of chemical attachment.
Co-reporter:Felix F. Schumacher, João P. M. Nunes, Antoine Maruani, Vijay Chudasama, Mark E. B. Smith, Kerry A. Chester, James R. Baker and Stephen Caddick
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 37) pp:NaN7269-7269
Publication Date(Web):2014/08/07
DOI:10.1039/C4OB01550A
The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody–drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody.
Co-reporter:Emily Knight, Eifion Robinson, Natalia Smoktunowicz, Rachel C. Chambers, Abil E. Aliev, Graham G. Inglis, Vijay Chudasama and Stephen Caddick
Organic & Biomolecular Chemistry 2016 - vol. 14(Issue 12) pp:NaN3274-3274
Publication Date(Web):2016/02/24
DOI:10.1039/C5OB02541A
Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM.
Co-reporter:Mark J. Cawley, F. Geoffrey N. Cloke, Richard J. Fitzmaurice, Stuart E. Pearson, James S. Scott and Stephen Caddick
Organic & Biomolecular Chemistry 2008 - vol. 6(Issue 15) pp:NaN2825-2825
Publication Date(Web):2008/06/06
DOI:10.1039/B801479E
Continuing efforts to establish a more general “user-friendly” protocol for the palladium-catalysed arylation of amines (Buchwald–Hartwig reaction) are described herein. Significant advances have been made through the use of the versatile (SIPr)Pd(methallyl)Cl complex in conjunction with the reliable base lithium hexamethyldisilazide (LHMDS).
Co-reporter:Olivier Thominet, James R. Baker, Hugh Britton, Zac C. Etheridge, Marco G. Soscia and Stephen Caddick
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 22) pp:NaN3712-3712
Publication Date(Web):2007/10/03
DOI:10.1039/B711196G
We present herein our recent efforts towards the synthesis of epoxydiynes which represent an unusual structural feature of the neocarzinostatin chromophore. A number of different routes to these epoxydiynes have been explored with varying success. Ultimately a concise and convergent approach was developed, which involved the addition of an allenyl zinc bromide to propargylic ketones/aldehydes followed by epoxide formation. This new protocol enabled us to synthesise a fully elaborated epoxydiyne which will find application for our studies towards the total synthesis of the NCS chromophore.
Co-reporter:Richard J. Fitzmaurice, Jenna M. Ahern and Stephen Caddick
Organic & Biomolecular Chemistry 2009 - vol. 7(Issue 2) pp:NaN237-237
Publication Date(Web):2008/11/26
DOI:10.1039/B819235A
A new and simple protocol for the direct functionalisation of aldehydes with concomitant conversion into ketones via C–C bond formation has been developed. The reaction effectively enables the direct C–H activation of an aldehyde by mixing of an aldehyde and a vinyl sulfonate under aerobic conditions or using hydrogen peroxide as a sub-stoichiometric reagent.
Co-reporter:Thomas Morris, David Sandham and Stephen Caddick
Organic & Biomolecular Chemistry 2007 - vol. 5(Issue 7) pp:NaN1027-1027
Publication Date(Web):2007/02/05
DOI:10.1039/B700804J
Functionalization of amino acid C- and N-termini with appropriate olefinic moieties allows for the generation of a peptidomimetic via a stereoselective cross-metathesis.
Co-reporter:Chris P. Ryan, Mark E. B. Smith, Felix F. Schumacher, Dina Grohmann, Danai Papaioannou, Gabriel Waksman, Finn Werner, James R. Baker and Stephen Caddick
Chemical Communications 2011 - vol. 47(Issue 19) pp:NaN5454-5454
Publication Date(Web):2011/04/05
DOI:10.1039/C1CC11114K
Controlling maleimide hydrolysis allows the modular construction of bromomaleimide-mediated bioconjugates which are either stable or cleavable in an aqueous, thiol-mediated reducing environment. The application of this methodology to reversible protein biotinylation, the irreversible labeling of peptide disulfide bonds and the assembly of stable, fluorescein-labelled glycoprotein mimics is described.
Co-reporter:Jonathan D. Wilden, Lynsey Geldeard, Chieh C. Lee, Duncan B. Judd and Stephen Caddick
Chemical Communications 2007(Issue 10) pp:NaN1076-1076
Publication Date(Web):2006/12/21
DOI:10.1039/B614604J
2,4,6-Trichlorophenol (TCP) sulfonate esters undergo effective aminolysis under conventional heating and microwave irradiation; the reactivity of these species is such that chemoselective transformations of PFP sulfonate esters can be achieved.
Co-reporter:Vijay Chudasama, Richard J. Fitzmaurice, Jenna M. Ahern and Stephen Caddick
Chemical Communications 2010 - vol. 46(Issue 1) pp:NaN135-135
Publication Date(Web):2009/11/13
DOI:10.1039/B914563J
Herein we report a mild, facile method for the preparation of 1,4-keto-sulfonates and sulfones on water. Further synthetic manipulations can result in products that are not readily accessed by hydroacylation of electron rich alkenes.
Co-reporter:Alexandra K. de K. Lewis, Stephen Caddick, Oriana Esposito, F. Geoffrey N. Cloke and Peter B. Hitchcock
Dalton Transactions 2009(Issue 35) pp:NaN7098-7098
Publication Date(Web):2009/07/21
DOI:10.1039/B907102D
The reaction between 2-chlorobenzylamine or 2-chlorobenzylalcohol and Pd(ItBu)2 (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) in benzene affords the dimeric complexes [Pd(ItBu)(μ-NH{2-CH2C6H4})]2 and [Pd(ItBu)(μ-O{2-CH2C6H4})]2; the latter has been structurally characterised. The syntheses, structural characterisation and reactivity of the Pd-NHC amine complexes [(ItBu)Pd(R-4-C6H4)(morpholine)Cl] (R = Me, OMe, CO2Me), intermediates in the Buchwald–Hartwig aryl amination reaction, are also reported.
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dimethyl-](http://img.cochemist.com/ccimg/110800/110796-98-0.png)
dimethyl-](http://img.cochemist.com/ccimg/110800/110796-98-0_b.png)
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