3-Fluoroazetidinecarboxylic Acids and trans,trans-3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar

Abstract

Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze. This paper describes the synthesis of 3-fluoro-Aze amino acids as hydroxy-Aze analogues which are not susceptible to aldol cleavage. 4-(Azidomethyl)-3-fluoro-Aze and 3,4-difluoroproline are new peptide building blocks. trans,trans-2,4-Dihydroxy-3-fluoroazetidine, an iminosugar, inhibits the growth of pancreatic cancer cells to a similar degree as gemcitabine.

Minimising conformational bias in fluoroprolines through vicinal difluorination

“…There is some precedent for these structures: syntheses of the (3R,4S)-difluorinated proline motif, 15 as in 6, and of the (3R,4R)-difluoromotif 16 (not shown) have been reported. Unfortunately, many synthetic steps were required to convert 3,4-dehydroproline to Cbz-protected (3R,4S)-3,4-difluoro-L-proline 16 and 3-deoxy-3-fluoro-1,2,5,6-di-O-isopropylidene-a-D-glucofuranose to N-benzyl protected (3R,4R)-3,4-difluoro-L-proline. 16 Here we report a short synthesis of 7 from (4R)-hydroxyproline, as well as NMR studies (amide cis : trans ratio and amide isomerisation rates) and preliminary theoretical calculations (ring pucker).…”

“…Unfortunately, many synthetic steps were required to convert 3,4-dehydroproline to Cbz-protected (3R,4S)-3,4-difluoro-L-proline 16 and 3-deoxy-3-fluoro-1,2,5,6-di-O-isopropylidene-a-D-glucofuranose to N-benzyl protected (3R,4R)-3,4-difluoro-L-proline. 16 Here we report a short synthesis of 7 from (4R)-hydroxyproline, as well as NMR studies (amide cis : trans ratio and amide isomerisation rates) and preliminary theoretical calculations (ring pucker). The results are compared to the equivalent data of the 4,4-difluorinated derivative 5.…”

Arabinofuranose‐derived positron‐emission tomography radiotracers for detection of pathogenic microorganisms

“…We made several attempts to synthesize these using an identical radiochemical strategy, without success. Several factors can impede a ring S N 2 fluorination reaction, including steric hindrance from neighboring positions, ring conformations that impede nucleophilic attack, and neighboring hydroxyl protecting groups that favor elimination 34, 35 . These 3‐position arabinofuranose‐derived analogs are a topic of future study.…”

Cell death and mitochondrial dysfunction induced by the dietary non-proteinogenic amino acid l-azetidine-2-carboxylic acid (Aze)

“…Significant conformational changes to protein structure are caused by Aze insertion, and these are discussed in detail elsewhere (Zagari et al 1990;Zagari et al 1994;Rubenstein 2008). Interestingly, Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine (Liu et al 2015), contributing further to the deleterious effects of Aze. Despite the low rate of Aze for L-proline substitution, adverse effects of Aze have been reported in plants (Fowden 1963;Verbruggen et al 1992;Lee et al 2016a), algae (Kim et al 2006) and in vivo models (Lane et al 1970;Rojkind 1973;Joneja 1981) and occur even in the presence of normal L-proline production (Fichman et al 2015).…”