- Synthesis and in vitro activity of long-chain 5'-O- [(alkoxycarbonyl)phosphinyl]-3'axido-3'-azido-3'-deoxythymidines against wild-type and AZT- and foscarnet-resistant strains of HIV-1
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Lipophilic esters of 3'-azido-3'-deoxy-5'-O- (carboxyphosphinyl)thymidine (PFA-AZT) were synthesized and tested for antiretroviral activity in CD4+ HT4-6C cells infected with either wild-type HIV-1(LAI), a PFA-resistant strain encoding a single-point mutation in reverse transcriptase (E89K), or an AZT-resistant clinical isolate (A018- post). Arbuzov condensation of 1-octadecyl, 1-eicosanyl, and 1-docosanyl chloroformate with trimethyl phosphate yielded the corresponding dimethyl long-chain alkyl triesters of PFA. Selective removal of one methyl group from the triesters with sodium iodide yielded monosodium salts, whereas treatment with bromotrimethylsaline cleaved both methyl groups while leaving the long- chain alkyl group intact. Neutralization of the resulting I(alkyloxy)carbonylphosphonic acids with 2 equiv of sodium methoxide afforded disodium salts of the phosphonic acid moiety. Similar chemistry was used to obtain the mono- and disodium salts of the cholesterol ester of FPA. Reaction of the triesters with phosphorous pentachloride, followed by coupling with AZT and O-demethylation with sodium iodide, afforded 3'-azido-3'-deoxy-5'-O- [[(1-octadecyloxy)carboxyl]phosphinyl]thymidine (9a), 3'-azido-3'-deoxy-5'- O-[[1-eocosanyloxy)carbonyl]phosphinyl]thymidine (9b), 3'-azido-3'-deoxy-5'- O[[1-docosanyloxy)carbonyl[phosphinyl]thymidine (9c), and 3'-azido-3'-deoxy- 5'-O-[[3β-cholest-4-enyloxy)carbonyl]phosphinyl]thymidine (9d). Concentrations of the 9a-d found to inhibit replication of wild-type HIV- 1(LAI) by 50% (OC50 values) as measured in a plaque reduction assay were in the 0.1-0.3 μM range as compared with 0.013 μM for AZT and 133 μM for PFA. The concentration at which toxicity was observed in 50% of the host cells (TC50 values) as measured by a visual grading scale of cellular morphology was 10 μM for 9a and 93, 32 μM for 9b, and 320 μM for 9c. Thus, the TC50/EC50 ratio or selectivity index (SI) was 100 for 9a, 230 for 9b, and 1000 for 9c but only 33 for 9d, suggesting that the straight-chained fatty alcohol esters were more therapeutically selective. Similar TC50 and SI values were obtained for rapidly dividing CEM lymphoblasts as for HT4-8C cells. In assays against E89K, 9a-c had mean EC50 values of 0.13, 0.009, and 0.17 μM, whereas the EC50 of PFA was >1000 μM and that of AZT was 0.009 μM; thus E89K was highly resistant to PFA but not cross-resistant to either AZT or the lipophilic PFA-AZT conjugates. In viral replication assays against the A018C-post isolate, the mean EC50 values of 9a-c were 0.30, 0.53, and 0.77 μM as compared with 2.9 μM for AZT and 65 μM for PFA; thus, the virus recovered from a patient pretreated with AZT was not cross- resistant to either PFA or 9a-c. A notable feature of these results was that, in addition to being >1000-fold more potent than PFA against the PFA- resistant mutant, the lipophilic PFA-AZT conjugates were more potent than PFA, as well as AZT, against AZT-resistant HIV-1.
- Rosowsky, Andre,Fu, Hongning,Pai, Niranjan,Mellors, John,Richman, Douglas D.,Hostetler, Karl Y.
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- Anti-HIV-Active Nucleoside Triphosphate Prodrugs
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We disclose a study on nucleoside triphosphate (NTP) analogues in which the γ-phosphate is covalently modified by two different biodegradable masking units and d4T as nucleoside analogue that enable the delivery of d4TTP with high selectivity in phosphate buffer (pH 7.3) and by enzyme-triggered reactions in human CD4+ T-lymphocyte CEM cell extracts. This allows the bypass of all steps normally needed in the intracellular phosphorylation. These TriPPPro-nucleotides comprising an acyloxybenzyl (AB; ester) or an alkoxycarbonyloxybenzyl (ACB; carbonate) in combination with an ACB moiety are described as NTP delivery systems. The introduction of these two different groups led to the selective formation of γ-(ACB)-d4TTPs by chemical hydrolysis and in particular by cell extract enzymes. γ-(AB)-d4TTPs are faster cleaved than γ-(ACB)-d4TTPs. In antiviral assays, the compounds are highly active against HIV-1 and HIV-2 in wild-type CEM/O cells and more importantly in thymidine kinase-deficient CD4+ T-cells (CEM/TK-).
- Jia, Xiao,Schols, Dominique,Meier, Chris
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p. 6003 - 6027
(2020/07/10)
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- Synthesis, physicochemical properties and biological activities of novel alkylphosphocholines with foscarnet moiety
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A series of alkylphosphocholines with foscarnet moiety was synthesized. The structure of these zwitterionic amphiphiles was modified in both polar and non-polar parts of surfactant molecule. Investigations of physicochemical properties are represented by the determination of critical micelle concentration, the surface tension value at the cmc and the surface area per surfactant head group utilising surface tension measurements. Hydrodynamic diameter of surfactant micelles was determined using the dynamic light scattering technique. Alkylphosphocholines exhibit significant cytotoxic, anticandidal (Candida albicans) and antiamoebal (Acanthamoeba spp. T4 genotype) activity. The relationship between the structure, physicochemical properties and biological activity of the tested compounds revealed that lipophilicity has a significant influence on biological activity of the investigated surfactants. More lipophilic alkylphosphocholines with octadecyl chains show cytotoxic activity against cancer cells which is higher than that of the compounds with shorter alkyl chains. The opposite situation was observed in case of anticandidal and antiamoebal activity of these surfactants. The most active compounds were found to have pentadecyl chains. The foscarnet analogue of miltefosine C15-PFA-C showed the highest anticandidal activity. The minimum value of anticandidal activity of this compound is 1,4 μM thus representing the highest anticandidal activity found within the group of alkylphosphocholines.
- Mrva, Martin,Bukovsky, Marián,Devínsky, Ferdinand,Garajová, Mária,Juhásová, Anna,Luká?, Milo?,Moj?i?, Ján,Moj?i?ová, Gabriela,Pisár?ik, Martin,Timko, Luká?
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- AMPHIPHILE PRODRUGS
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Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolised to a biologically active agent; and X is selected from the group consisting of R, or up to three R moieties attached to a linker, Y1, Y2 or Y3, wherein R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; Y1 is a linker group which covalently attached to an R group at one site and is attached to A at a further independent site; Y2 is a linker group which is covalently attached to two R groups at two independent sites and is attached to A at a further independent site; and Y3 is a linker group which is covalently attached to three R groups at three independent sites and is attached to A at a further independent site. Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed. In preferred embodiments A is dopamine or a 5-fluorouracil prodrug.
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Page/Page column 0177; 0178; 0179
(2019/06/12)
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- Antiviral compounds and methods of administration
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The invention provides lipophilic phosphonoacid/nucleoside conjugates that exhibit exceptional antiviral activity, including activity against drug-resistant HIV strains. Compounds of the invention include phosphonoacid/nucleoside conjugates where the carboxyl group and phosphonyl groups of the phosphonacid are esterified whereby the compound contains at least one lipophilic group and at least one nucleoside group.
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Page/Page column 20
(2008/06/13)
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- A safe and efficient procedure to prepare alkyl and alkoxyalkyl chlorides and dichlorides by catalytic decomposition of the corresponding alkyl and alkoxyalkyl chloroformates and bischloroformates with hexabutylguanidinium chloride
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Small amounts of hexabutylguanidinium chloride (0.01 mol%) decomposes pure chloroformates or bischloroformates with different lengths of carbon chains by a semicontinuous process to diminish run-away risk, leading to chloride compounds with high yield and purity.
- Violleau,Thiebaud,Borredon,Le Gars
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p. 367 - 373
(2007/10/03)
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- Antitumor activity of a piperidine phospholipid
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A piperidine phospholipid ((±)-2-[hydroxy][[1-octa-decyloxycarbonylpiperidin-3-yl]methoxy-phosp hinyl]oxy]-N,N,N,trimethylethaniminium hydroxide inner salt, SDZ 62-826) has been prepared that exhibited weak direct cytotoxicity and strong macrophage-induced cytotoxicity in vitro against a variety of murine and one human tumor cell lines. This compound was found to be as effective as ET-18-OCH3 and SRI 62-834, phospholipids with both strong direct and macrophage-induced cytotoxicity, in increasing survivors and reducing tumor volume when given either orally or intravenously in the mouse MethA fibrosarcoma model. These findings suggest that the macrophage-induced cytotoxicity exhibited by ET-18-OCH3 and other phospholipids may play an important role in this tumor model.
- Houlihan,Lee,Munder,Handley,Nemecek,Jaeggi,Winslow
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p. 1384 - 1388
(2007/10/02)
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- Reduction et photoreduction de derives de l'acide carbonique influence de l'hexamethylphosphorotriamide
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Photoreduction and reduction of carbonic acid derivatives in HMPT have been compared.The highest yield of alkane was obtained from N,N-dimethylthiocarbamates either by the photochemical method or by reduction with a dissolved metal.Competitive reactions have been characterized: - during the photoreduction not only the alkane but products of a photo-Fries rearrangement and products of a homolytic cleavage were detected; - basic reactions can compete with the reduction of carbonic acid derivatives by sodium in HMPT.
- Dembele, Albert,Deshayes, Henri,Pete, Jean-Pierre
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p. 671 - 680
(2007/10/02)
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