Formation of phosphoester bonds in phosphoglyceride synthesis

Stepanov, A.F.; Швец, В. И.

doi:10.1016/0009-3084(86)90123-4

Cited by 20 publications

(5 citation statements)

References 255 publications

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“…The importance of phospholipids in physiological processes, in particular as mediators in signal transduction, has stimulated the development of methods for the efficient chemical synthesis of structurally well defined phospholipids and their analogs as enzyme inhibitors and drug candidates . These routes include the phosphorylation of alcohols using the phosphoramidites originally developed for oligonucleotide chemistry , and the use of activating reagents such as 2,4,6-triisopropylbenzenesulfonyl chloride (TPS). , These routes are somewhat limited by the availability of the required intermediates. To circumvent these problems the chlorophosphate route described by Eibl and Woolley for the synthesis of long-chain diradylglycerol phospholipids was explored.…”

Section: Resultsmentioning

confidence: 99%

“…32 These routes include the phosphorylation of alcohols using the phosphoramidites originally developed for oligonucleotide chemistry 33,34 and the use of activating reagents such as 2,4,6-triisopropylbenzenesulfonyl chloride (TPS). 14,35 These routes are somewhat limited by the availability of the required intermediates. To circumvent these problems the chlorophosphate route described by Eibl and Woolley 36 for the synthesis of long-chain diradylglycerol phospholipids was explored.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Structure−Activity Relationships, and the Effect of Polyethylene Glycol on Inhibitors of Phosphatidylinositol-Specific Phospholipase C fromBacillus cereus

et al. 1996

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Substrate analog inhibitors of Bacillus cereus phosphatidylinositol-specific phospholipase C (PI-PLC) were synthesized and screened for their suitability to map the active site region of the enzyme by protein crystallography. Analogs of the natural substrate phosphatidylinositol (PI) were designed to examine the importance of the lipid portion and the inositol phosphate head group for binding to the enzyme. The synthetic compounds contained pentyl, hexyl, or hexanoyl and octyl lipid chains at the sn-1 and sn-2 positions of the glycerol backbone and phosphonoinositol, phosphonic acid, methyl phosphonate, phosphatidic acid, or methyl phosphate at the sn-3 position. The most hydrophobic compound, dioctyl methyl phosphate 14, was also the best inhibitor with an IC50 of 12 microM. In a series of dihexyl lipids, compounds with phosphonoinositol head groups inhibited more strongly than those that do not contain inositol but are otherwise identical. Compound 29, a short-chain lipid with a phosphonoinositol head group, was found to be a competitive inhibitor and the most potent in this series with an IC50 of 18 microM (Ki = 14 microM). Analogs with dihexyl chains were better inhibitors than those with dihexanoyl chains, presumably because the ether-linked lipids are more hydrophobic than the ester-linked lipids. No appreciable difference in inhibition was found between a phosphonoinositol lipid and the corresponding difluorophosphonoinositol lipid. Inositols and inositol derivatives that do not contain lipid moieties show IC50s about 3 orders of magnitude above those of the short-chain lipids. In this group, glucosaminyl(alpha 1-->6)-D-myo-inositol inhibited more strongly than myo-inositol, which in turn is a better inhibitor than inositol phosphate. The addition of polyethylene glycol (PEG-600) resulted in a marked decrease in inhibition by the short-chain lipids, but had little effect on the water-soluble head group analogs. This is accounted for in terms of solubilization of the amphipathic inhibitors by PEG. Since PEG is required in the crystallization, these data indicate that the best strategy for obtaining enzyme inhibitor complexes is to start by cocrystallizing PI-PLC with the head group analogs. The next step is to synthetically add the shortest possible hydrophobic moieties to the analogs and cocrystallize these with the enzyme. This strategy may be applicable to other lipolytic enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis, Structure−Activity Relationships, and the Effect of Polyethylene Glycol on Inhibitors of Phosphatidylinositol-Specific Phospholipase C fromBacillus cereus

et al. 1996

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“…Molecular substitutions relative to dipalmitoyl phosphatidylcholine (DPPC) confer resistance to phospholipase A 1 , A 2 , and D, as well as partial resistance to phospholipase C in DEPN-8 through steric hindrance [41]. The synthesis of phosphoglycerol derivatives 13a and 13b was realized by standard phosphoglycerol chemistry [51][52][53] (Fig. [34,35,42,44].…”

Section: Iiib Synthesis Of Phospholipase-resistant Phospholipid (Phmentioning

confidence: 99%

Novel Phospholipase-Resistant Lipid/Peptide Synthetic Lung Surfactants

Notter¹,

Schwan²,

Wang³

et al. 2007

MRMC

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Animal-derived drugs are currently widely-used to treat clinical lung surfactant deficiency, but synthetic surfactants have significant advantages as pharmaceutical agents. This article examines exogenous surfactants containing novel synthetic phospholipase-resistant lipids of extremely high surface activity. Mixtures of these lipid analogs with purified native surfactant apoproteins are detailed as a proof of concept for related fully-synthetic surfactants containing laboratory-produced peptides. The chemistry and biophysics of relevant lipid analogs and peptides are reviewed in the context of developing new synthetic drugs of utility for patients with surfactant deficiency or lung injury-related surfactant dysfunction.

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“…96 ' 184>196 Such derivatives have been discussed in the literature in connection with the elucidation of the structures of natural complexes incorporating in their structure biopolymers and lipids. 8 Previously they were synthesised only by methods of classical phospholipid chemistry. The new suggestions based on the use of effective phosphorylation procedures apparently merit extensive use and can lead to progress in the study of such complex systems.…”

Section: O O-mentioning

confidence: 99%