Lipophilic Pyrylium Salts in the Synthesis of Efficient Pyridinium-Based Cationic Lipids, Gemini Surfactants, and Lipophilic Oligomers for Gene Delivery

Ilies, Marc A.; Seitz, W. A.; Johnson, Betty H.; Ezell, Edward L.; Miller, Aaron L.; Thompson, E. Brad; Balaban, Alexandrù T.

doi:10.1021/jm0601755

Cited by 103 publications

(154 citation statements)

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“…The potential use of surfactants in pharmaceutical and biological applications 1,2,3,4,5,6 makes the evaluation of cytotoxicity and environmental behaviour of great importance.…”

Section: Introductionmentioning

confidence: 99%

pH-Sensitive Surfactants from Lysine: Assessment of Their Cytotoxicity and Environmental Behavior

et al. 2012

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The toxicity and environmental behavior of new pH-sensitive surfactants from lysine are presented. Three different chemical structures are studied: surfactants with one amino acid and one alkyl chain, surfactants with two amino acids on the polar head and one alkyl chain, and gemini surfactants. The pH sensitivity of these compounds can be tuned by modifying their chemical structures. Cytotoxicity has been evaluated using erythrocytes and fibroblast cells. The toxic effects against these cells depend on the hydrophobicity of the molecules as well as their cationic charge density. The effect of hydrophobicity and cationic charge density on toxicity is different for each type of cells. For erythrocytes, the toxicity increases as hydrophobicity and charge density increases. Nevertheless, for fibroblasts cationic charge density affects cytotoxicity in the opposite way: the higher charge density, the lower the toxicity. The effect of the pH on hemolysis has been evaluated in detail. The aquatic toxicity was established using Daphnia magna. All surfactants yielded EC50 values considerably higher than that reported for cationic surfactants based on quaternary ammonium groups. Finally, their biodegradability was evaluated using the CO2 headspace test (ISO 14593). These lysine derivatives showed high levels of biodegradation under aerobic conditions and can be classified as “readily biodegradable compounds”.

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“…The potential use of surfactants in pharmaceutical and biological applications 1,2,3,4,5,6 makes the evaluation of cytotoxicity and environmental behaviour of great importance.…”

Section: Introductionmentioning

confidence: 99%

pH-Sensitive Surfactants from Lysine: Assessment of Their Cytotoxicity and Environmental Behavior

et al. 2012

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“…Tosylate (4) was condensed with 4-amino-1-butanol in N,N-dimethylformamide (DMF) at 90°C to yield 5. Protection of the amino nitrogen in 5 with a Ntert-butoxycarbonyl (Boc) group, esterifcation of the resulting alcohol (6) as the tosylate, and condensation of the tosylate (7) and 4-amino-1-butanol gave the corresponding primary alcohol (8). After protecting the amino nitrogen of 8 with N-Boc, the terminal hydroxyl group was mesylated with methanesulfonyl chloride (MsCl) to yield 10.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment of 4,9-diaza-4,9-di-(tert-butoxycarbonyl)dodecane-1,12-diamine 8) with ptoluenesulfonyl chloride (TsCl) in the presence of triethylamine (TEA) in CH 2 Cl 2 gave p-toluenesulfonamide compound 18 in 49% yield, and then the terminal primary amino group in 18 was converted to guanidino compound (20) by treating 18 with N,NЈ-bis(tert-butoxycarbonyl)-S-methylisothiourea in CH 2 Cl 2 . Finally, the Boc protecting groups of 20 were removed using 36% HCl in tetrahydrofuran (THF) to give the desired compound TsSPMG (2a).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Water-Soluble Polyamine Derivatives Effective as N-Methyl-D-aspartate Receptor Antagonists

Masuko

Yoshida

Metori

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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Three pharmacologically-defined classes of ionotropic glutamate receptors were originally named according to their agonist selectivity: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. The NMDA receptor consists of at least two distinct subunits, NR1 and NR2 1) (Fig. 1A). Each subunit has three transmembrane domains (M1, M3, and M4) plus a cytoplasm-facing re-entrant membrane loop (M2). The M2 loop region in the NR1 and NR2 subunits is a critical determinant of divalent cation permeability and Mg 2ϩ block. NR1 is a single gene product expressed as eight alternatively spliced mRNAs, and NR2A, NR2B, NR2C and NR2D are distinct gene products. NMDA receptors probably consist of tetrameric subunit assemblies that have different physiological and pharmacological properties depending on the specific NR2 subunit. In the central nervous system, NMDA receptors play critical roles in a variety of neurophysiological phenomena, including neurodevelopment, synaptic plasticity, and excitotoxicity, because of their high permeability to Ca 2ϩ . Neurodegeneration associated with a variety of acute and chronic disorders (e.g., ischemic stroke, Parkinson's disease, Alzheimer's disease and dementia) is due in part to overactivation of NMDA receptors (Fig. 1B). Inhibitors of NMDA receptors have thus been developed as anticonvulsants and neuroprotective agents.Polyamines (putrescine, spermidine and spermine) are ubiquitously present in prokaryotic and eukaryotic cells. In the central nervous system, specific interactions of polyamines with several structurally and functionally distinct types of cation channels have been reported previously. 2)Among these, the most striking are the blockade of some types of K ϩ channels and the modulation of NMDA receptors. Spermine has complex effects on NMDA receptors, including two types of stimulation and one type of voltage-dependent blockade. One of the effects of spermine is "glycineindependent" stimulation, observed in the presence of saturating concentrations of glutamate and glycine. With recombinant NMDA receptors, this type of stimulation is observed only at receptors containing splice variants of NR1 that lack the exon-5 insert, expressed together with the NR2B subunit.3) Inhibition by extracellular spermine is strongly voltage-dependent, being more pronounced at hyperpolarized and M2, and an intracellular C-terminal domain. The glycine and glutamate binding pockets involving residues from the N-terminal domain and from the M3-M4 loop of NR1 and NR2 subunits, respectively. (B) Excitotoxicity is thought to be a major mechanism contributing to neurodegeneration during central nervous system, ischemia, trauma and other neurological disorders. Excitotoxicity is thought to result from an excessive synaptic release of glutamate. Also, it is generally accepted that the NMDA receptor plays a key role in mediating at least certain aspects of glutamate neurotoxicity, possibly owing to their high Ca 2ϩ permeability. When Ca 2ϩ overloaded, such pro...

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“…The liposomes containing lipid 2d were the least active. It was found that heterocyclic cationic lipids containing imidazolinium (Solodin et al, 1995) or pyridinium polar heads (Ilies et al, 2006) reveal a higher TE and a reduced level of cytotoxicity in comparison with the classical transfectants. To study the influence of this type of heterocyclic polar head on the TE, the cholesterol-based lipids containing heterocyclic amine connected to the cholesterol residue via urethane (4a-f, 6a), ether (5a-5h) and ester linkers (6b-f) were synthesized (Gao & Hui, 2001;Bajaj et al, 2008c;Medvedeva et al, 2009).…”

Section: Monocationic Lipidsmentioning

confidence: 99%

Non-Viral Gene Delivery Systems Based on Cholesterol Cationic Lipids: Structure-Activity Relationships

Маслов¹,

Зенкова²

2011

Non-Viral Gene Therapy

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Lipophilic Pyrylium Salts in the Synthesis of Efficient Pyridinium-Based Cationic Lipids, Gemini Surfactants, and Lipophilic Oligomers for Gene Delivery

Cited by 103 publications

References 64 publications

pH-Sensitive Surfactants from Lysine: Assessment of Their Cytotoxicity and Environmental Behavior

pH-Sensitive Surfactants from Lysine: Assessment of Their Cytotoxicity and Environmental Behavior

Synthesis of Water-Soluble Polyamine Derivatives Effective as N-Methyl-D-aspartate Receptor Antagonists

Non-Viral Gene Delivery Systems Based on Cholesterol Cationic Lipids: Structure-Activity Relationships

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