Urea derivatives on the move: cytokinin‐like activity and adventitious rooting enhancement depend on chemical structure

Ricci, Ada; Bertoletti, Cristina

doi:10.1111/j.1438-8677.2008.00165.x

Cited by 30 publications

(20 citation statements)

References 92 publications

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“…FCF is a synthetic urea derivative with strong cytokinin activity in plants [17]. Deemed as an agent with relatively short half-life and low in vivo toxicity, FCF is a government-approved fertilizer used in fruit horticulture.…”

Section: Discussionmentioning

confidence: 99%

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In Silico Docking of Forchlorfenuron (FCF) to Septins Suggests that FCF Interferes with GTP Binding

Angelis

Karasmanis

et al. 2014

PLoS ONE

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Septins are GTP-binding proteins that form cytoskeleton-like filaments, which are essential for many functions in eukaryotic organisms. Small molecule compounds that disrupt septin filament assembly are valuable tools for dissecting septin functions with high temporal control. To date, forchlorfenuron (FCF) is the only compound known to affect septin assembly and functions. FCF dampens the dynamics of septin assembly inducing the formation of enlarged stable polymers, but the underlying mechanism of action is unknown. To investigate how FCF binds and affects septins, we performed in silico simulations of FCF docking to all available crystal structures of septins. Docking of FCF with SEPT2 and SEPT3 indicated that FCF interacts preferentially with the nucleotide-binding pockets of septins. Strikingly, FCF is predicted to form hydrogen bonds with residues involved in GDP-binding, mimicking nucleotide binding. FCF docking with the structure of SEPT2-GppNHp, a nonhydrolyzable GTP analog, and SEPT7 showed that FCF may assume two alternative non-overlapping conformations deeply into and on the outer side of the nucleotide-binding pocket. Surprisingly, FCF was predicted to interact with the P-loop Walker A motif GxxxxGKS/T, which binds the phosphates of GTP, and the GTP specificity motif AKAD, which interacts with the guanine base of GTP, and highly conserved amino acids including a threonine, which is critical for GTP hydrolysis. Thus, in silico FCF exhibits a conserved mechanism of binding, interacting with septin signature motifs and residues involved in GTP binding and hydrolysis. Taken together, our results suggest that FCF stabilizes septins by locking them into a conformation that mimics a nucleotide-bound state, preventing further GTP binding and hydrolysis. Overall, this study provides the first insight into how FCF may bind and stabilize septins, and offers a blueprint for the rational design of FCF derivatives that could target septins with higher affinity and specificity.

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Section: Discussionmentioning

confidence: 99%

“…FCF is a synthetic plant cytokinin that consists of a chlorinated pyridine and a phenol ring joined together by a urea group [17]. FCF was fortuitously discovered to reversibly affect the localization and morphology of septins in the budding yeast Saccharomyces cerevisiae [18].…”

Section: Introductionmentioning

confidence: 99%

In Silico Docking of Forchlorfenuron (FCF) to Septins Suggests that FCF Interferes with GTP Binding

Angelis

Karasmanis

et al. 2014

PLoS ONE

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“…[1][2][3][4][5][6][7][8][9][10][11] The classical approaches to preparet hese molecules are based on the use of toxic reactants, such as phosgenea nd its derivatives or oxalyl chloride and its derivatives. [1][2][3][4][5][6][7][8][9][10][11] The classical approaches to preparet hese molecules are based on the use of toxic reactants, such as phosgenea nd its derivatives or oxalyl chloride and its derivatives.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Oxidative Carbonylation of Amino Moieties to Ureas, Oxamides, 2‐Oxazolidinones, and Benzoxazolones

et al. 2015

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The direct syntheses of ureas, oxamides, 2-oxazolidinones, and benzoxazolones by the oxidative carbonylation of amines, β-amino alcohols, and 2-aminophenols allows us to obtain high value added molecules, which have a large number of important applications in several fields, from very simple building blocks. We have found that it is possible to perform these transformations using the PdI2 /KI catalytic system in an ionic liquid, such as 1-butyl-3-methylimidazolium tetrafluoroborate, as the solvent, the solvent/catalyst system can be recycled several times with only a slight loss of activity, and the product can be recovered easily by crystallization.

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“…FCF promotes cell division and is involved in cell growth and differentiation. It has a cytokinesis inhibitor effect in higher concentrations [1]. It was incidentally found that FCF causes rapid and reversible deformation of septin filament on the bud neck in yeast [2].…”

Section: Introductionmentioning

confidence: 99%

Forchlorfenuron Disrupts SEPT9_i1 Filaments and Inhibits HIF-1

2013

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Forchlorfenuron (FCF) is a synthetic plant cytokinin that has been shown to alter yeast and mammalian septin organization. Septins are a highly conserved family of GTP-binding cytoskeletal proteins. Mammalian septins are involved in diverse cellular processes including tumorigenesis. We have been studying the interaction between septin 9 isoform 1 (SEPT9_i1) and hypoxia inducible factor-1α (HIF-1α), the oxygen regulated subunit of HIF-1. HIF-1 is a key transcription factor in the hypoxic responses pathway, and its activation has been observed in carcinogenesis and numerous cancers. SEPT9_i1/HIF-1α interaction plays an important role in upregulation of HIF-1 transcriptional activity by preventing HIF-1α’s ubiquitination and degradation leading to increased tumor growth and angiogenesis. We tested the hypothesis whether FCF affects SEPT9_i1 filamentous structures and consequently HIF-1 pathway in cancer cells. We showed that FCF suppresses tumorigenic properties, including proliferation, migration and transformation, in prostate cancer cells. FCF did not alter SEPT9_i1 steady state protein expression levels but it affected its filamentous structures and subcellular localization. FCF induced degradation of HIF-1α protein in a dose- and time-dependent manner. This inhibition was also shown in other common cancer types tested. Rapid degradation of HIF-1α protein levels was accompanied by respective inhibition in HIF-1α transcriptional activity. Moreover, HIF-1α protein half-life was markedly decreased in the presence of FCF compared with that in the absence of FCF. The FCF-induced degradation of HIF-1α was mediated in a significant part via the proteasome. To the best of our knowledge, this is the first demonstration of specific manipulation of septin filaments by pharmacological means having downstream inhibitory effects on the HIF-1 pathway.

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Urea derivatives on the move: cytokinin‐like activity and adventitious rooting enhancement depend on chemical structure

Cited by 30 publications

References 92 publications

In Silico Docking of Forchlorfenuron (FCF) to Septins Suggests that FCF Interferes with GTP Binding

In Silico Docking of Forchlorfenuron (FCF) to Septins Suggests that FCF Interferes with GTP Binding

Catalytic Oxidative Carbonylation of Amino Moieties to Ureas, Oxamides, 2‐Oxazolidinones, and Benzoxazolones

Forchlorfenuron Disrupts SEPT9_i1 Filaments and Inhibits HIF-1

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