The Bohlmann–Rahtz route to functionalised pyridine scaffolds and their use in library synthesis

Bashford, Katherine E.; Burton, Matthew; Cameron, Stuart; Cooper, Anthony; Hogg, R.; Kane, Peter D.; MacManus, David A.; Matrunola, Christopher A.; Moody, Christopher J.; Robertson, Avril A. B.; Warne, Mark R.

doi:10.1016/s0040-4039(03)00034-0

Cited by 36 publications

(18 citation statements)

References 22 publications

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“…24 Thus, commercially available N-Boc isonipecotic acid 4 was converted to known β-keto ester 6 through a simple two-step sequence (coupling of Meldrum's acid followed by ethanolysis). 25 Alternatively, condensation of the acid chloride of 6 with potassium ethyl malonate in the presence of a magnesium chloride-triethylamine base system also gave 7 . 26 With the requisite β-keto ester 7 in hand, the formation of pyrazole core was explored with commercially available 4-isopropyl phenylhydrazine.…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

Wang

Sinn

et al. 2011

J. Med. Chem.

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Virtual screening targeting the urokinase receptor (uPAR) led to (3R)-4-cyclohexyl-3-(hexahydrobenzo[d][1,3]dioxol-5-yl)-N-((hexahydrobenzo[d][1,3]dioxol-5-yl)methyl)butan-1-aminium 1 (IPR-1) and 4-(4-((3,5-dimethylcyclohexyl)carbamoyl)-2-(4-isopropylcyclohexyl)pyrazolidin-3-yl)piperidin-1-ium 3 (IPR-69). Synthesis of an analog of 1, namely 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC50 near 30 μM. Both compounds blocked angiogenesis with IC50 of 3 μM. Compounds 2 and 3 inhibited cell growth with IC50 of 6 and 18 μM and induced apoptosis. Biochemical assays revealed lead-like properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 hours. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.

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Section: Resultsmentioning

confidence: 99%

Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

Wang

Sinn

et al. 2011

J. Med. Chem.

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“…24 The conditions for the Bohlmann-Rahtz synthesis of scaffold 15 reacted the enamine 16 with butynone 2b in ethanol at reflux to give a single regioisomeric pyridine product in 77% yield. Hydrolysis of ester 15 gave acid 17 that was then taken on to scale up.…”

Section: Pyridine Libraries and Scaffoldsmentioning

confidence: 99%

The Bohlmann-Rahtz Pyridine Synthesis: From Discovery to Applications

Bagley¹,

Glover²,

Merritt³

2007

Synlett

205

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The results of our research into the Bohlmann-Rahtz pyridine synthesis are summarized. The historic discovery of this reaction and its mechanism are discussed; followed by recent improvements in methodology, such as Brønsted and Lewis acid catalysis, microwave assistance, process in a continuous flow reactor, and incorporation into multicomponent and tandem reactions. Applications of these methods in the synthesis of pyrido[2,3-d]pyrimidines, combinatorial pyridine libraries, heterocyclic a-and gamino acids, a-helix mimetics, and complex natural products are discussed, along with a consideration of future perspectives.

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“…The pyrazole core was prepared by condensation of 1,3-dicarbonyl enol ethers with hydrazines. Thus, commercially available isonipecotic acid was protected to the N-Boc version 6 , which was converted to known β-keto ester 8 through a simple two-step sequence (coupling of Meldrum's acid followed by ethanolysis) (42). With the requisite β-keto ester 8 in hand, the formation of the pyrazole core was explored with commercially available hydrazine.…”

Section: Resultsmentioning

confidence: 99%

Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor

et al. 2013

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The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here we evaluate the binding and biological activity of a new class of pyrrolidinone (3) and piperidinone (4) compounds, along with derivatives of previously-identified pyrazole (1) and propylamine (2) compounds. Competition assays revealed that the compounds displaced a fluorescently-labeled peptide (AE147-FAM) with inhibition constant Ki ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics simulations and free energy calculations suggested pyrazole-based 1a and piperidinone-based 4 adopt different binding modes, despite their similar two-dimensional structures. In cells, compounds 1b and 1f showed significant inhibition of breast MDA-MB-231 and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but 4b exhibited no cytotoxicity even at concentrations of 100 μM. 1f impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while 4b inhibited only invasion. 1f inhibited gelatinase (MMP-9) activity in a concentration-dependent manner, while 4b showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinone and piperidinone (3 and 4b) had no effect. Annexin V staining suggested that the effect of pyrazole-based 1f on proliferation was due to cell killing through an apoptotic mechanism.

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The Bohlmann–Rahtz route to functionalised pyridine scaffolds and their use in library synthesis

Cited by 36 publications

References 22 publications

Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

Virtual Screening Targeting the Urokinase Receptor, Biochemical and Cell-Based Studies, Synthesis, Pharmacokinetic Characterization, and Effect on Breast Tumor Metastasis

The Bohlmann-Rahtz Pyridine Synthesis: From Discovery to Applications

Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor

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