Arthur F. Rosenthal

Preparation of immunologically responsive liposomes with phosphonyl and phosphinyl analogs of lecithin.

Abstract Liposomes, which release trapped glucose marker upon incubation with an appropriate antiserum and complement source, have been prepared from analogs of lecithin that cannot serve as substrates for phospholipases A, B, C, or D. These results confirm and extend previous studies with radioactive liposomes which have suggested that direct attack on membrane phospholipids by the above enzymatic activities may not be responsible for complement-dependent damage.

A study of phospholipase a inhibition by glycerophosphatide analogs in various systems

Abstract The effects of several synthetic lecithin and cephalin analogs containing ether, phosphonate and/or phosphinate moieties on the phospholipase A reaction were studied, using A. piscivorus venom as the enzyme source. A variety of systems was used, including aqueous, ether-activated, and deoxycholate-activated reactions. The effects of the phosphonate analogs were variable and appeared to depend primarily on purely physical factors. However, a phosphinate analog of lecithin, C 18 H 37 ,OCH 2 CH(OC 16 H 33 )CH 2 P(O)(O − )CH 2 CH 2 N + (CH 3 ) 3 , was found to be a competitive inhibitor of Phospholipase A in all systems tried, with the exception of deoxycholate-activated reactions.

Synthesis of DL-2,3-diacyloxypropylphosphonylcholines from DL-2,3-diacyloxyiodopropanes

The chemical synthesis of racemic diacyloxypropylphosphonylcholines having octanoyl, myristoyl, oleoyl and stearoyl groups is described. The route involved reaction of dioactanoyloxy-dimyristoyloxy-dioleoyloxy-, and distearoyloxpropyliodide with tris (trimethylsilyl) phosphite to yield the corresponding bis (trimethylsilyl) phosphonate. Removal of the trimethylsilyl groups by neutral aqueous hydrolysis gave the free diacylpropylphosphonic acids, which, when treated with choline toluenesulfonate, yielded the desired dioctanoyloxy-, dimyristoyloxy-, dioleoyloxy-, and distearoyloxypropylphosphonylcholines. The paper also describes the synthesis of 2-octadecyleicosylphosphorylcholine.

Isosteres of natural phosphates. 4. The synthesis of phosphonic acid analogues of phosphatidic acid and acyldihydroxyacetone phosphate

The chemical synthesis of 3,4-diacyloxybutyl-1-phosphonic acids having palmitoyl and oleoyl groups is described. These were prepared by reaction of the appropriate 3,4-diacyloxybutyl-1-bromide with tris(trimethylsilyl) phosphite followed by mild hydrolysis of the trimethyl-silyl groups from the phosphonic acid. Also reported is the preparation of 4-palmitoyl-3-oxobutyl-1-phosphonic acid by the acylation of 4-hydroxy-3-oxobutyl-1-phosphonic acid. This latter compound is an isosteric analogue of acyldihydroxyacetone phosphate.

Synthesis of optically active diether phosphinate analogs of lecithin

Abstract Syntheses are described of the optically active diether phosphinate analogs of lecithin l -ROCH 2 CH(OR)CH 2 CH 2 P(O) (O−)CH 2 CH 2 +(CH 3 ) 3 and l -ROCH 2 CH(OR)-CH 2 CH 2 (O) (O−)CH 2 CH 2 CH 2 N+(CH 3 ) 3 (R = C 18 H 37 ), which are respectively partially and completely isosteric, and of the same enantiomeric form, as the natural phospholipid. The following synthetic route was used: 1, 2, 5, 6-diisopropylidene d -mannitol → D-mannitol 3,4-di( p -methylbenzyl) ether → D-mannitol 1,2,5,6-tetraoctadecyl-3,4-di-( p -methylbenzyl) ether → D-mannitol 1,2,5,6-tetraoctadecyl ether → D-2,3-dioctadecoxyglyceraldehyde → l -3,4-dioctadecoxy-I-butene → L-3,4-dioctadecoxy-I-butanol → L-3,4-dioctadecoxy-I-bromobutane. From the l -bromo intermediate the lecithin analogs were prepared by procedures previously reported for the corresponding racemic compounds.

A synthetic phosphinate–phosphonate liponucleotide analogue

A nine-step synthesis of the nucleotide coenzyme analogue (1) is reported, providing the first example of the nucleotide coenzyme analogue containing three isosteric C-P bonds, and of a phospinate–phosphonate nucleotide of any type.

Synthesis of long-chain ethers by phase-transfer. Improved preparation of D-mannitol 1,2,5,6-tetraoctadecyl ether

Abstract The synthesis of D-mannitol 1,2,5,6-tetraoctadecyl ether by phase-transfer is reported, illustrating that this synthetic mode is as applicable to the preparation of long-chain ethers as to short-chain compounds, Dry-column purification of the intermediate D-mannitol 1,2,5,6-tetraoctadecyl-3,4,-di-(p-methylbenzyl) ether is described.

A completely isosteric non-hydrolyzable analog of lecithin

Abstract The chemical synthesis of the first completely isosteric, completely non-hydro-lyzable lecithin analog, C18H37OCH2CH(OC18H37)CH2CH2P(O)(O−)CH2CH2CH2N+(CH3)3 is described. The synthetic route used was the following: RP(O) (OR′)CH2CH=CH2 → RP(O) (OR′)CH2CH2CH2OH → RP(O) (OR′)CH2CH2CH2OMs → RP(O) (OR′)CH2CH2CH2N+(CH3)3-OMs → RP(O) (O−)CH2CH2CH2N+(CH3)3 R = C18H37OCH2CH(OC18H37)CH2CH2- R′ = (CH3)2CH- Ms = CH3SO2-

Synthesis of phosphonate and ether analogs of rac-phosphatidyl-L-serine

The chemical synthesis of four phosphonate-containing phosphatidylserine analogs namely, L-serine (+/-)-[2,3-bis(hexadecyloxy) and 2,3-bis(Palmitoyloxy)-propyl] phosphonates, and L-serine (+/-)-[3,4-bis(hexadecyloxy and 3,4-bis(palmitoyloxy)-butyL]phosphonates is descirbed. (+/-)-2,3-Bis(hexadecyloxy) and 2,3-bis(palmitoyloxy)-prophylphosphonic acids and (+/-)-3,4-bis(hexadecyloxy)butylphosponic acid were prepared by reaction of tris(trimethylsily) phosphite on the corresponding haloalkane. Condensation of the above phosphonic acids or (+/-)-3,4-bis(palmitoyloxy)butylphosphonic acid with N-carboxy-L-serine dibenzyl ester in the presence of trichloroacetonitrile or triisopropylbenzenesulfonyl chloride yielded the protected serine intermediates, which on hydrogenolysis gave the desired L-serine analogs. By a similar route, 1,2-dihexadecyl-rac-glycero-3-phosphoric acid was converted to 1,2-dihexadecyl-rac-glycerophospho-L-serine (L-serine (+/-)-2,3-bis(hexadecyloxy)propyl hydrogen phosphate(ester).

Improved qualitative screening test for cystinuria and homocystinuria

Abstract The test for cystinuria is improved by substituting borohydride for cyanide as a reducing agent.