- Synthesis, self-aggregation and biological properties of alkylphosphocholine and alkylphosphohomocholine derivatives of cetyltrimethylammonium bromide, cetylpyridinium bromide, benzalkonium bromide (C16) and benzethonium chloride
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A series of alkylphosphocholine and alkylphosphohomocholine derivatives of cetyltrimethylammonium bromide, cetylpyridinium bromide, benzalkonium bromide (C16) and benzethonium chloride have been synthesized. Their physicochemical properties were also investigated. The critical micelle concentration (cmc), the surface tension value at the cmc (γcmc), and the surface area at the surface saturation per head group (Acmc) were determined by means of surface tension measurements. The prepared compounds exhibit significant cytotoxic, antifungal and antiprotozoal activities. Alkylphosphocholines and alkylphosphohomocholines possess higher antifungal activity against Candida albicans in comparison with quaternary ammonium compounds in general. However, quaternary ammonium compounds exhibit significantly higher activity against human tumor cells and pathogenic free-living amoebae Acanthamoeba lugdunensis and Acanthamoeba quina compared to alkylphosphocholines. The relationship between structure, physicochemical properties and biological activity of the tested compounds is discussed.
- Luká?, Milo?,Mrva, Martin,Garajová, Mária,Moj?i?ová, Gabriela,Varinská, Lenka,Moj?i?, Ján,Sabol, Marián,Kubincová, Janka,Haragová, Hana,Ondriska, Franti?ek,Devínsky, Ferdinand
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- Synthesis and biological activity of dialkylphosphocholines
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A series of dialkylphosphocholines were prepared and evaluated for their biological activity. The antiprotozoal activity was determined against Acanthamoeba lugdunensis. Compound 15 exhibited excellent trophocidal activity. None of the tested dialkylphosphocholines exhibited better fungicidal activity against Candida albicans than miltefosine. The antineoplastic activity was determined against HeLa. The most cytotoxic was compound 10, which was more active against tumor cells as against normal cells.
- Lukac, Milos,Mrva, Martin,Fischer-Fodor, Eva,Lacko, Ivan,Bukovsky, Marian,Miklasova, Natalia,Ondriska, Frantisek,Devinsky, Ferdinand
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scheme or table
p. 6346 - 6349
(2010/06/11)
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- The biocidal activity of some phosphate cationic surfactant complexes
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A SERIES of oil soluble surface active agents based on A triethanolamine hydrochloride and alkylated phosphoric acid was synthesized and characterized as surface active agents. Transition metal complex of Cu(II), Co(II) and Fe(ΠI) was synthesized throughout direct complexation between the transition metal ions and the synthesized surfactants. The chemical structures of these compounds were confirmed using elemental analysis, FTIR and Η-NMR spectroscopy. The synthesized compounds were oil soluble and comprise good interfacial tension and emulsion stability towards oil-water systems. The biological activity of the synthesized surfactants and their metal complexes was applied as biocides for different types of bacteria and fungi. The biocidal activity of these compounds showed good activity towards the studied microorganisms. The experimental results of the surface a:Id biocidal activities were greatly influenced by the nature of the transition metal ions, as well as the hydrophobic chain length. A comparison between the influence of the metal ion type and the alkyl chain length on their biological activity was done.
- Zaky
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experimental part
p. 31 - 38
(2010/04/05)
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- Fatty alcohol phosphates are subtype-selective agonists and antagonists of lysophosphatidic acid receptors
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A more complete understanding of the physiological and pathological role of lysophosphatidic acid (LPA) requires receptor subtype-specific agonists and antagonists. Here, we report the synthesis and pharmacological characterization of fatty alcohol phosphates (FAP) containing saturated hydrocarbon chains from 4 to 22 carbons in length. Selection of FAP as the lead structure was based on computational modeling as a minimal structure that satisfies the two-point pharmacophore developed earlier for the interaction of LPA with its receptors. Decyl and dodecyl FAPs (FAP-10 and FAP-12) were specific agonists of LPA2 (EC50 = 3.7 ± 0.2 μM and 700 ± 22 nM, respectively), yet selective antagonists of LPA3 (Ki = 90 nM for FAP-12) and FAP-12 was a weak antagonist of LPA1. Neither LPA1 nor LPA3 receptors were activated by FAPs; in contrast, LPA2 was activated by FAPs with carbon chains between 10 and 14. Computational modeling was used to evaluate the interaction between individual FAPs (8 to 18) with LPA2 by docking each compound in the LPA binding site. FAP-12 displayed the lowest docked energy, consistent with its lower observed EC50. The inhibitory effect of FAP showed a strong hydrocarbon chain length dependence with C12 being optimum in the Xenopus laevis oocytes and in LPA3-expressing RH7777 cells. FAP-12 did not activate or interfere with several other G-protein-coupled receptors, including S1P-induced responses through S1P1.2,3.5 receptors. These data suggest that FAPs are ligands of LPA receptors and that FAP-10 and FAP-12 are the first receptor subtype-specific agonists for LPA2.
- Virag, Tamas,Elrod, Don B.,Liliom, Karoly,Sardar, Vineet M.,Parrill, Abby L.,Yokoyama, Kazuaki,Durgam, Gangadhar,Deng, Wenlin,Miller, Duane D.,Tigyi, Gabor
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p. 1032 - 1042
(2007/10/03)
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- Alkyl and alkoxyethyl antineoplastic phospholipids
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Two series of phosphodiester ether lipid analogs with (N- methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (9-19) was evaluated in vitro against a panel of six human tumor xenografts and in two biochemical, mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Analogs 13, 14, 17, and 19 showed activity in the in vitro tests. Specifically, 14 and 17 were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while 13 and 19 possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (17) has an N- methylpiperidino head group and a C16 alkyl chain. In the mechanism-based tests 11 showed weak inhibitory activity in the cdc25 phosphatase screen.
- Koufaki, Maria,Polychroniou, Vanessa,Calogeropoulou, Theodora,Tsotinis, Andrew,Drees, Markus,Fiebig, Heiner H.,LeClerc, Sophie,Hendriks, Hans R.,Makriyannis, Alexandros
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p. 2609 - 2614
(2007/10/03)
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- Inhibition of human erythrocyte membrane phosphatidylinositol 4-kinase by phospholipid analogues
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Analogues of phosphatidylinositol (PtdIns, 1) have been synthesized to investigate the structural requirements for inhibition of a PtdIns 4-kinase obtained from human erythrocyte membranes. While the presence of either D-1 or D-3 stereochemistry in the inositol moiety greatly influences the degree of inhibition produced by PtdIns analogues, the stereochemistry of the glycerol moiety is of little consequence. Neither structural feature however, makes a significant contribution to binding affinity. Competitive inhibitory activity was found to be retained (or even enhanced) in substantially simpler analogues consisting of 1 or 2 hydrocarbon chains attached to a charged phosphate head group, such as in the phosphatidic acids, 24 and 26. The observation that the phosphatidylinositol 4-phosphate (PtdIns 4P) and phosphatidic acid analogues (eg, 16 or 17, and 26 respectively) inhibit PtdIns 4-kinase may suggest that such species have a regulatory role in PtdIns turnover.
- Young,Downes,Jones,Milliner,Rana,Ward
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p. 537 - 549
(2007/10/02)
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- Gemini surfactants: A new class of self-assembling molecules
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"Gemini surfactant" is a name assigned to a family of synthetic amphiphiles possessing, in sequence, a long hydrocarbon chain, an ionic group, a spacer, a second ionic group, and another hydrocarbon tail. Intramolecular chain/chain association was inhibited through the use of rigid spacers, thereby averting self-assembly into conventional micellar structures. Aggregation of the geminis was investigated by (a) surface tension, (b) film-balance methods, (c) dynamic light scattering, (d) 1H and 23Na NMR, and (e) spectral changes in an adsorbed dye. Among the more striking properties of geminis, one should cite the following: (a) a higher critical micelle concentration (according to surface tension and NMR) for geminis with two long chains of 16-20 carbons than that for shorter-chain analogs; (b) the lift-off areas in monomolecular films that are several times those of phospholipids, indicating that the geminis lie absolutely horizontally at the air/water interface; and (c) the formation of only small micelles, despite the potential to grow, polymer-like, into extended strands. It is argued that geminis, especially the longer-chain members, engage in self-coiling or submicellar aggregation when first exposed to water. Self-assembly into micelles and adsorption at the air/water interface then take place over hours or days at 23 °C but much more rapidly at 50 °C. Spectral data provide strong evidence for submicellar structures.
- Menger,Littau
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p. 10083 - 10090
(2007/10/02)
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- Synthesis of Alkyl Dihydrogenphosphate by the Reaction of Alcohols and Silyl Polyphosphate
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Alkyl dihydrogenphosphates were readily prepared by phosphorylation of alcohols with trimethylsilyl polyphosphate of polyphosphorylated silica-gel.
- Okamoto, Yoshiki
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p. 3393 - 3394
(2007/10/02)
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- Nucleoside conjugates. 6. Synthesis and comparison of antitumor activity of 1-β-D-arabinofuranosylcytosine conjugates of corticosteroids and selected lipophilic alcohols
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Five new P1-(steroid-21-yl)-P2-(1-β-D-arabinofuranosylcytosin-5'-yl)pyrophosphat es (ara-CDP-steroids), five 1-β-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P1-(alkyl)-P2-(1-β-D-arabinofuranosylcytosin-5'-yl)pyrophosphate (ara-CDP-alkyl esters) have been prepared and evaluated against L1210 lymphoid leukemia in culture and in mice (C3D2F1/J). These include ara-CDP-11-deoxycorticosterone, ara-CDP-cortisone, ara-CDP-corticosterone, ara-CDP-cortexolone, and ara-CDP-prednisone, ara-CMP hexadecyl ester, ara-CMP 1-cyclohexylmethyl ester, ara-CMP 1-adamantylmethyl ester, ara-CMP 2-(1-adamanthyl)ethyl ester, ara-CMP 2-chloroethyl ester, ara-CDP hexadecyl ester, and ara-CDP 1-cyclohexylmethyl ester. The in vitro antitumor results indicated that ara-CDP-steroids were as active as the previously reported ara-CMP-steroids and that ara-CMP and ara-CDP-alkyl esters were less growth inhibiting than ara-CDP-steroids and ara-C. However, the in vivo antitumor results indicated that ara-CDP-steroids were generally less effective than the previous monophosphate derivatives. Among them ara-CDP-corticosterone and the known ara-CDP-cortisol showed greater efficacy than ara-C with ILS value of 152% and 209%, respectively, at the optimal dose of 40 and 80 (mg/kg)/day for 9 days, while that of ara-C was 138% at the optimum dose of 9.2 (mg/kg)/day. Generally, ara-CMP alkyl esters, given ip to the L1210 leukemic mice, were found to be toxic and ineffective. However, ara-CDP hexadecyl ester showed marginal activity (ILS, 38%). These preliminary results support the thesis that the ara-C conjugates of this type may require a lipophilic and naturally occurring moiety for improved efficacy.
- Hong,Kirisits,Nechaev,Buchheit,West
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p. 171 - 177
(2007/10/02)
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