Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
Org Biomol Chem ; 20(42): 8209-8211, 2022 Nov 02.
Article in English | MEDLINE | ID: mdl-36239212

ABSTRACT

Herein, we report the development of a novel route to tricyclic lactam products via a facile aza-[4 + 2] cycloaddition of catalytically generated acyliminium ions. Employing a Ca(NTf2)2/nBu4NPF6 catalyst system in low loadings, a range of diverse fused ring systems can be synthesised in predominantly good yields.


Subject(s)
Cycloaddition Reaction , Catalysis , Ions
2.
Chem Commun (Camb) ; 58(60): 8376-8379, 2022 Jul 26.
Article in English | MEDLINE | ID: mdl-35792361

ABSTRACT

The regio and stereoselective hydrosilylation of a variety of homopropargylic alcohols and their derivatives is described. The reaction is tolerant to a variety of sterically and electronically varied substrates, affording only the E-vinyl silane as a sole regioisomer. The application of the resultant vinyl silanes towards the diastereoselective synthesis of tetrasubstituted oxetanes is demonstrated.


Subject(s)
Alcohols , Silanes , Ethers, Cyclic
3.
Chemistry ; 28(48): e202201107, 2022 Aug 26.
Article in English | MEDLINE | ID: mdl-35642626

ABSTRACT

A range of highly functionalized polycyclic fragments have been synthesized, employing a catalytic dehydrative cyclization. A range of nucleophiles are shown to be successful, with the reaction producing numerous high value motifs.


Subject(s)
Cyclization , Catalysis
4.
Thromb Haemost ; 122(7): 1115-1129, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35253142

ABSTRACT

Cucurbitacins are dietary compounds that have been shown to elicit a range of anti-tumour, anti-inflammatory and anti-atherosclerotic activities. Originally identified as signal transducer and activator of transcription, STAT, inhibitors, a variety of mechanisms of action have since been described, including dysregulation of the actin cytoskeleton and disruption of integrin function. Integrin outside-in signalling and cytoskeletal rearrangements are critical for the propagation of stable thrombus formation and clot retraction following platelet adhesion at the site of vessel damage. The effects of cucurbitacins on platelet function and thrombus formation are unknown. We report for the first time anti-platelet and anti-thrombotic effects of cucurbitacins B, E and I in human platelets. Treatment of platelets with cucurbitacins resulted in attenuation of platelet aggregation, secretion and fibrinogen binding following stimulation by platelet agonists. Cucurbitacins were also found to potently inhibit other integrin- and cytoskeleton-mediated events, including adhesion, spreading and clot retraction. Further investigation of cytoskeletal dynamics found treatment with cucurbitacins altered cofilin phosphorylation, enhanced activation and increased F actin polymerisation and microtubule assembly. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function.


Subject(s)
Platelet Glycoprotein GPIIb-IIIa Complex , Thrombosis , Blood Platelets/metabolism , Cucurbitacins/metabolism , Cucurbitacins/pharmacology , Cytoskeleton/metabolism , Humans , Microtubules/metabolism , Platelet Aggregation , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Thrombosis/metabolism
5.
Org Lett ; 23(11): 4463-4467, 2021 Jun 04.
Article in English | MEDLINE | ID: mdl-34018758

ABSTRACT

We describe, for the first time, a highly regioselective hydrosilylation of propargylic amines. The reaction utilizes a PtCl2/XantPhos catalyst system to deliver hydrosilanes across the alkyne to afford multifunctional allylic amines in high yields. The reaction is tolerant to a wide variety of functional groups and provides high value intermediates with two distinct functional handles. The synthetic applicability of the reaction has been shown through the synthesis of diverse ambiphilic aziridines.

6.
ChemSusChem ; 14(7): 1696-1699, 2021 Apr 09.
Article in English | MEDLINE | ID: mdl-33605021

ABSTRACT

Herein, we report a sustainable, modular, rapid and high-yielding transformation to afford densely functionalized 5-aminooxazoles and thiazoles. The reaction is tolerant to a wide range of functional groups and is typically complete in under 30 min. Furthermore, the described transformation is inherently green in relation to the catalyst and solvent choice as well as producing environmentally benign alcoholic by-products.

7.
J Org Chem ; 85(8): 5615-5628, 2020 04 17.
Article in English | MEDLINE | ID: mdl-32208694

ABSTRACT

Herein we report our full investigation into the calcium catalyzed generation and trapping of N-acyliminium ions from readily available 3-hydroxyisoindolinones. We have successfully employed a range of traditional nucleophiles including carbon, nitrogen, and sulfur containing reactive partners. The reaction is tolerant to a wide range of functionalities and provides high value scaffolds in good to excellent yields.

8.
J Org Chem ; 85(2): 301-305, 2020 Jan 17.
Article in English | MEDLINE | ID: mdl-31775003

ABSTRACT

A mild and facile Peterson olefination has been developed employing low catalyst loading of the Brønsted acid HNTf2. The reactions are typically performed at room temperature, with the reaction tolerant to a range of useful functionalities. Furthermore, we have extended this methodology to the synthesis of enynes.

9.
Chem Commun (Camb) ; 55(57): 8317-8320, 2019 Jul 11.
Article in English | MEDLINE | ID: mdl-31257381

ABSTRACT

A rapid and functionally tolerant calcium catalysed Hosomi-Sakurai reaction has been realised. Employing 1 mol% calcium, allylated isoindolinones can be synthesised in high yields and the reaction is shown to be tolerant to a range of medicinally relevant functional groups including heterocycles. The synthetic utility of the reaction has been shown, and a plausible reaction mechanism is provided.

10.
Eur J Med Chem ; 177: 316-337, 2019 Sep 01.
Article in English | MEDLINE | ID: mdl-31158747

ABSTRACT

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 µM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.


Subject(s)
Enzyme Inhibitors/pharmacology , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Pyridines/pharmacology , Pyrimidinones/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor/methods , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Molecular Structure , Protein Binding , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrimidinones/metabolism , Structure-Activity Relationship
11.
J Med Chem ; 59(4): 1388-409, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-26741168

ABSTRACT

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Nuclear Proteins/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Repressor Proteins/antagonists & inhibitors , Caco-2 Cells , Cell Membrane Permeability , Enzyme Inhibitors/pharmacokinetics , Humans , Jumonji Domain-Containing Histone Demethylases/chemistry , Jumonji Domain-Containing Histone Demethylases/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Pyrimidinones/pharmacokinetics , Repressor Proteins/chemistry , Repressor Proteins/metabolism
12.
Org Lett ; 17(1): 10-3, 2015 Jan 02.
Article in English | MEDLINE | ID: mdl-25513732

ABSTRACT

A rapid and stereodefined synthesis of MIDA-boryl vinylsilanes has been achieved through the hydrosilylation of an alkynylboronic ester. The E products which contain a silyl and boryl group can be selectively cross-coupled in a two-step bidirectional sequence to provide a rapid and high-yielding synthesis of complex styrenes.


Subject(s)
Silanes/chemistry , Stilbenes/chemical synthesis , Styrenes/chemical synthesis , Vinyl Compounds/chemistry , Boronic Acids/chemistry , Esters , Molecular Structure , Stereoisomerism , Stilbenes/chemistry , Styrenes/chemistry
13.
Chem Commun (Camb) ; 50(26): 3501-4, 2014 Apr 04.
Article in English | MEDLINE | ID: mdl-24557001

ABSTRACT

The highly syn-selective hydrosilylation of allylic alcohols was developed which, following oxidation, provided 1,3 alcohols containing two contiguous stereocentres. Through judicious choice of silane the complementary anti-selective hydrosilylation was also developed. This protocol was applied to the synthesis of an all syn polyketide stereotriad.

14.
Org Biomol Chem ; 11(44): 7662-6, 2013 Nov 28.
Article in English | MEDLINE | ID: mdl-24108362

ABSTRACT

A base mediated isomerisation-allylation protocol of 1,3-disubstituted propenols has been established. The use of diaryl and aryl-silyl substrates is reported alongside the use of substituted allyl bromides. Mechanistic experiments have also been conducted to elucidate the reaction pathway.

15.
Org Biomol Chem ; 11(27): 4488-502, 2013 Jul 21.
Article in English | MEDLINE | ID: mdl-23715614

ABSTRACT

A facile and user-friendly protocol has been developed for the selective synthesis of E-vinyl silanes derived from propargylic alcohols using a PtCl2/XPhos catalyst system. The reaction is generally high yielding and provides a single regioisomer at the ß-position with E-alkene geometry. The reaction is extremely tolerant of functionality and has a wide scope of reactivity both in terms of alkynes and silanes used. The catalyst loading has been investigated and it is found that good reactivity is observed at extremely low catalyst loadings. This methodology has also been extended to a one-pot hydrosilylation Denmark-Hiyama coupling.


Subject(s)
Alkynes/chemistry , Platinum/chemistry , Propanols/chemistry , Silanes/chemical synthesis , Alkenes/chemistry , Catalysis , Silanes/chemistry , Stereoisomerism
16.
J Org Chem ; 77(4): 2058-63, 2012 Feb 17.
Article in English | MEDLINE | ID: mdl-22235747

ABSTRACT

A one-pot isomerization-Claisen protocol has been developed for the synthesis of highly substituted allylsilanes. Monosilylated divinyl ethers can be isomerized using a cationic iridium(I) catalyst followed by a thermal Claisen rearrangement to provide the allylsilanes in excellent yields and diastereoselectivities.

17.
Chem Commun (Camb) ; 47(39): 11104-6, 2011 Oct 21.
Article in English | MEDLINE | ID: mdl-21909537

ABSTRACT

A highly regioselective hydrosilylation of propargylic alcohols has been developed using an in situ prepared PtCl(2)/XPhos catalyst system. The reaction is tolerant of many functional groups and exhibits excellent regio and geometric selectivity.

SELECTION OF CITATIONS
SEARCH DETAIL
...