Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been ...evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
The carboline ring system is an important pharmacophore found in a number of biologically important targets. Development of synthetic routes for the preparation of these compounds is important in ...order to prepare a range of analogues containing the carboline heterocyclic moiety. A manganese dioxide mediated one-pot method starting with an activated alcohol and consisting of alcohol oxidation, Pictet-Spengler cyclisation, and oxidative aromatisation, offers a convenient process that allows access to β-carbolines. This one-pot process for the preparation of methyl 9H-pyrido3,4-bindole-1-carboxylate has subsequently been used as the key step in the synthesis of alangiobussinine and a closely related analogue.
The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each ...pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo2,3-bpyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure-activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 IKKα Ki = 10 nM; IKKβ Ki = 680 nM and SU1349 IKKα Ki = 16 nM; IKKβ Ki = 3352 nM) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents.The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo2,3-bpyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure-activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 IKKα Ki = 10 nM; IKKβ Ki = 680 nM and SU1349 IKKα Ki = 16 nM; IKKβ Ki = 3352 nM) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents.
Sphingosine kinase enzymes (SK1 and SK2) catalyze the conversion of sphingosine into sphingosine 1-phosphate and play a key role in lipid signaling and cellular responses. Mapping of isoform amino ...acid sequence differences for SK2 onto the recently available crystal structures of SK1 suggests that subtle structural differences exist in the foot of the lipid-binding “J-channel” in SK2, the structure of which has yet to be defined by structural biology techniques. We have probed these isoform differences with a ligand series derived from the potent SK1-selective inhibitor, PF-543. Here we show how it is possible, even with relatively conservative changes in compound structure, to systematically tune the activity profile of a ligand from ca. 100-fold SK1-selective inhibition, through equipotent SK1/SK2 inhibition, to reversed 100-fold SK2 selectivity, with retention of nanomolar potency.
The inhibitory-kappaB kinases (IKKs) IKKα and IKKβ play central roles in regulating the non-canonical and canonical NF-κB signalling pathways. Whilst the proteins that transduce the signals of each ...pathway have been extensively characterised, the clear dissection of the functional roles of IKKα-mediated non-canonical NF-κB signalling versus IKKβ-driven canonical signalling remains to be fully elucidated. Progress has relied upon complementary molecular and pharmacological tools; however, the lack of highly potent and selective IKKα inhibitors has limited advances. Herein, we report the development of an aminoindazole-pyrrolo2,3-bpyridine scaffold into a novel series of IKKα inhibitors. We demonstrate high potency and selectivity against IKKα over IKKβ in vitro and explain the structure–activity relationships using structure-based molecular modelling. We show selective target engagement with IKKα in the non-canonical NF-κB pathway for both U2OS osteosarcoma and PC-3M prostate cancer cells by employing isoform-related pharmacodynamic markers from both pathways. Two compounds (SU1261 IKKα Ki = 10 nM; IKKβ Ki = 680 nM and SU1349 IKKα Ki = 16 nM; IKKβ Ki = 3352 nM) represent the first selective and potent pharmacological tools that can be used to interrogate the different signalling functions of IKKα and IKKβ in cells. Our understanding of the regulatory role of IKKα in various inflammatory-based conditions will be advanced using these pharmacological agents.
IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a ...complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.
Titanium enolates from chiral
N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions ...with acetals. Related oxazolidinethiones also afforded good results, but the corresponding oxazolidinones resulted completely unselective for such reactions, which proves that an exocyclic C
S bond is essential to attain a synthetically useful stereocontrol.
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The stereochemical outcome of the Lewis acid-mediated glycolate addition of the titanium enolates from protected N-hydroxyacetyl-4-isopropyl-1,3-thiazolidine-2-thiones to dimethyl and dibenzyl ...acetals depends on the hydroxyl protecting group. Particularly, the pivaloyl protected glycolate derivative provides the reluctant anti adducts in high yields and diastereomeric ratios, which can be isolated and further converted in enantiomerically pure form to β-methoxy or β-benzyloxy α-pivaloyloxy carbonyl fragments in a straightforward manner.
Prostate cancer is the second most prevalent cancer in men. Activation of the NF-ҡB pathway is involved in the development of prostate cancer resistance to current therapies and contributes to the ...high mortality rate associated with this cancer. NF-ҡB has been shown to be inactive in the cytosol when bound with IҡB proteins. Activation of the IҡB kinase (IKK) complex degrades IҡB via phosphorylation and subsequent targeting by the proteasome, which enables transcription of NF-ҡB into the nucleus to control gene expression. The IKK-complex is formed by the two catalytic subunits IKKα and IKKβ and a regulatory subunit, NEMO, which is essential for its activation. The key interaction between these three units occurs in a localised region characterised by a hexapeptide sequence (LDWSWL). Disruption of the IKK-complex suppresses the transcription of NF-ҡB and can suppress tumour development. This project focuses on the suppression of this pathway using two different approaches. Firstly, the disruption of the interaction of NEMO with the two catalytic subunits was attempted using short modified-hexapeptide sequences based upon LDWSWL. We sequentially varied the six residues to identify the most efficacious sequence that disrupts the IKK-complex with the view to producing drug-like peptidomimetics with increased stability, potency and an improved pharmacokinetic profile. The synthesis of these novel peptides was accomplished by solid phase peptide synthesis and using SP-HPLC for their purification. A novel and simple method based fluorescence techniques was investigated to evaluate the interaction of NEMO with these hexapeptide sequences. The second approach to disrupt NF-ҡB activation was investigated by designing and developing selective heterocyclic ATP competitive inhibitors against IKKα and IKKβ. β-carbolines are known to be selective inhibitors of IKKβ, but other carboline-derived scaffolds (α-, γ- or δ-carbolines) have not yet been explored. Our efforts have been focussed on the synthesis of these scaffolds and to produce potent and selective drug-like molecules for the inhibition of IKKα and IKKβ. Our results have shown that a derivative of β-carboline inhibits IKKβ with high potency and selectivity and that the α-carboline offers an extremely promising scaffold for the synthesis of very potent IKKα-inhibitors.
Prostate cancer is the second most prevalent cancer in men. Activation of the NF-ҡB pathway is involved in the development of prostate cancer resistance to current therapies and contributes to the ...high mortality rate associated with this cancer. NF-ҡB has been shown to be inactive in the cytosol when bound with IҡB proteins. Activation of the IҡB kinase (IKK) complex degrades IҡB via phosphorylation and subsequent targeting by the proteasome, which enables transcription of NF-ҡB into the nucleus to control gene expression. The IKK-complex is formed by the two catalytic subunits IKKα and IKKβ and a regulatory subunit, NEMO, which is essential for its activation. The key interaction between these three units occurs in a localised region characterised by a hexapeptide sequence (LDWSWL). Disruption of the IKK-complex suppresses the transcription of NF-ҡB and can suppress tumour development. This project focuses on the suppression of this pathway using two different approaches. Firstly, the disruption of the interaction of NEMO with the two catalytic subunits was attempted using short modified-hexapeptide sequences based upon LDWSWL. We sequentially varied the six residues to identify the most efficacious sequence that disrupts the IKK-complex with the view to producing drug-like peptidomimetics with increased stability, potency and an improved pharmacokinetic profile. The synthesis of these novel peptides was accomplished by solid phase peptide synthesis and using SP-HPLC for their purification. A novel and simple method based fluorescence techniques was investigated to evaluate the interaction of NEMO with these hexapeptide sequences. The second approach to disrupt NF-ҡB activation was investigated by designing and developing selective heterocyclic ATP competitive inhibitors against IKKα and IKKβ. β-carbolines are known to be selective inhibitors of IKKβ, but other carboline-derived scaffolds (α-, γ- or δ-carbolines) have not yet been explored. Our efforts have been focussed on the synthesis of these scaffolds and to produce potent and selective drug-like molecules for the inhibition of IKKα and IKKβ. Our results have shown that a derivative of β-carboline inhibits IKKβ with high potency and selectivity and that the α-carboline offers an extremely promising scaffold for the synthesis of very potent IKKα-inhibitors.
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