New Synthesis of β-Lactams by Ethylene Extrusion from Spirocyclopropane Isoxazolidines

New Synthesis of β-Lactams by Ethylene Extrusion from Spirocyclopropane Isoxazolidine

A New Bicyclic Dipeptide Isostere with Pyrrolizidinone Skeleton

The synthesis of a new conformationally constrained Gly-(s-cis)Pro Turn Mimetic (GPTM) in both racemic and enantiomerically pure forms and their incorporation into peptides 18, 21, and 24 are reported. The synthetic strategy adopted to assemble the bicyclic pyrrolizidinone skeleton is based on the 1,3-dipolar cycloaddition of the cyclic nitrone 4a derived from proline and acrylamide, followed by a reductive cleavage/cyclization domino process. The enantiomerically pure GPTMs are obtained by synthesis and separation of diastereomeric intermediates containing (1R)-1-phenylethylamine as chiral auxiliary. Analysis of pseudotripeptides 18, 21, and 22 by FT-IR and NMR shows that the amide proton of GPTM derivatives 21 is intramolecularly hydrogen bonded in CDCl3, while DMSO was shown to disrupt this hydrogen bond

A New Bicyclic Dipeptide Isostere with Pyrrolizidinone Skeleton

The synthesis of a new conformationally constrained Gly-(s-cis)Pro Turn Mimetic (GPTM) in both racemic and enantiomerically pure forms and their incorporation into peptides 18, 21, and 24 are reported. The synthetic strategy adopted to assemble the bicyclic pyrrolizidinone skeleton is based on the 1,3-dipolar cycloaddition of the cyclic nitrone 4a derived from proline and acrylamide, followed by a reductive cleavage/cyclization domino process. The enantiomerically pure GPTMs are obtained by synthesis and separation of diastereomeric intermediates containing (1R)-1-phenylethylamine as chiral auxiliary. Analysis of pseudotripeptides 18, 21, and 22 by FT-IR and NMR shows that the amide proton of GPTM derivatives 21 is intramolecularly hydrogen bonded in CDCl3, while DMSO was shown to disrupt this hydrogen bond

A New Bicyclic Dipeptide Isostere with Pyrrolizidinone Skeleton

The synthesis of a new conformationally constrained Gly-(s-cis)Pro Turn Mimetic (GPTM) in both racemic and enantiomerically pure forms and their incorporation into peptides 18, 21, and 24 are reported. The synthetic strategy adopted to assemble the bicyclic pyrrolizidinone skeleton is based on the 1,3-dipolar cycloaddition of the cyclic nitrone 4a derived from proline and acrylamide, followed by a reductive cleavage/cyclization domino process. The enantiomerically pure GPTMs are obtained by synthesis and separation of diastereomeric intermediates containing (1R)-1-phenylethylamine as chiral auxiliary. Analysis of pseudotripeptides 18, 21, and 22 by FT-IR and NMR shows that the amide proton of GPTM derivatives 21 is intramolecularly hydrogen bonded in CDCl3, while DMSO was shown to disrupt this hydrogen bond

Affinity of FED6 and uptake of [¹⁸F]FED6 in NSCLC cell lines.

A. IC50 values of FED6 obtained from measuring changes in p-EGFR Y1068 in NSCLC cell lines following incubation with FED6 for 3 h. Data are mean IC50 ± SE obtained from three separate experiments. B. Protein normalised uptake of [18F]FED6 in NSCLC cell lines following 1 h incubation with 0.22MBq [18F]FED6. C. Protein expression of total EGFR, and ABC transporters ABCG2 and ABCB1 in NSCLC cells. MCF7MX and 3T3-MDR1 were used as positive controls for ABCG2 and ABCB1 expression, respectively.</p

[¹⁸F]FED6 uptake in ABC transporter expressing cells.

A. Protein normalised uptake of [18F]FED6 in 3T3 and 3T3-MDR1 cells, following 1 h incubation with 0.22MBq of [18F]FED6, with or without pre-treatment with zosuquidar at 0.3 μM for 1 h. B. Protein normalised uptake of [18F]FED6 in MCF7 and MCF7MX cells, following 1 h incubation with 0.22MBq of [18F]FED6, with or without pre-treatment with 10 μM fumitremorgin C (FTC) for 1 h. Data are mean ± SE of triplicates, repeated twice. Statistical differences between data obtained following an unpaired t-test are indicated on graph; (** = P < 0.01).</p

The effect of cyanoquinoline inhibitors on growth of ABC transporter-proficient or ABC transporter-deficient cell lines.

<p>The effect of cyanoquinoline inhibitors on growth of ABC transporter-proficient or ABC transporter-deficient cell lines.</p

Comparative affinities FED20, gefitinib and FED6 in TKI sensitive and resistant NSCLC cell lines and [¹⁸F]FED20 uptake in the cell lines.

<p>Typical of p-EGFR Y1068 and EGFR protein expression following 3 h incubation with increasing concentrations of A. FED20, B. gefitinib, or C. FED6 in PC9 and PC9ER cells; summary IC50 values for all cell lines determined from densitometry analysis of p-EGFR Y1068 in the western blots are shown. D. Protein normalised uptake of [¹⁸F]FED20 in TKI sensitive and resistant cells following 1 h incubation with 0.55 MBq of [¹⁸F]FED20 (low specific activity; 7.3 GBq/μmol). E. Protein normalised uptake of [¹⁸F]FED20 in TKI sensitive and resistant cells following 1 h incubation with 0.74 MBq of [¹⁸F]FED20 (higher specific activity; 52 GBq/μmol). (* = p < 0.05, ** = P < 0.01).</p

Efflux ratios of cyanoquinoline compounds in caco2 transwell assay.

<p>A. Efflux ratios of selected cyanoquinoline compounds. B. Efflux ratios of FED6 and vinblastine with or without pre-treatment with 10 mg/mL of verapamil or 10μM of fumitremorgin C (FTC) for 1 h. All data shows mean ± SE of triplicates, repeated twice. Statistically significant differences between data obtained following an unpaired t-test are indicated on graph; (* = p < 0.05, ** = P < 0.01).</p

Growth inhibitory effect associated with a series of cyanoquinoline molecules in 3T3, 3T3-MDR1, MCF7, and MCF7MX cells.

<p>A. Ratios of GI50 values in 3T3-MDR1 over GI50 values in 3T3 cells with and without pre-treatment with zosuquidar (zos). B. Ratios of GI50 values in MCF7MX over GI50 values in MCF7 cells with and without pre-treatment with fumitremorgin C (FTC). Data indicate mean ratios ± SE of ratios obtained from three separate experiments.</p