Nucleoside Conjugates. 15. Synthesis and Biological Activity of Anti-HIV Nucleoside Conjugates of Ether and Thioether Phospholipids

Abstract

A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (2) 2',3'-dideoxycytidine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (3), and AZT 5'-diphosphate-rac-1-O-tetradecyl-2-O-palmitoylglycerol (4). The conjugates form micelles by sonication (mean diameters ranging 6.8-55.5 nm). Conjugate 1 protected 80% of HIV-infected CEM cells as low as 0.58 microM and lost the protection at 180 microM due to prevailing cytotoxicity, while the conjugate started to show the cytotoxicity at 100 microM. Pharmacokinetics studies showed a significant increase of half-life values (t1/2) of AZT and AZddU2 (respective t1/2 = 5.69 and 6.5 h) after administration of conjugates 1 and 2, while those after administration of AZT and AZddU were 0.28 and 0.89 h, respectively. The fractions of the prodrugs 1 and 2 converted to the parent compounds AZT and AZddU were 36% and 55%, respectively. The results indicate that AZT and AZddU thioether lipid conjugates 1 and 2 warrant further investigation.

Alkylthioglycerol Prodrugs of Foscarnet: Synthesis, Oral Bioavailability and Structure–Activity Studies in Human Cytomegalovirus-, Herpes Simplex Virus Type 1- and Human Immunodeficiency Virus Type 1-Infected Cells

“…Bioreversible prodrugs incorporating thioether lipids and having efficacy equal to corresponding O-ether derivatives have been reported (Hong et al, 1996). We now report the synthesis and antiviral evaluation of a series ofl-S-alkyl-sn-thioglycero-3-PFA conjugates (5a-e; Fig.…”

Synthesis of sulfur-containing glycerophospholipids

“…Sulfur-containing sn-1 phospholipids encompass a wide spectrum of biological roles ranging from synthetic lung surfactants [15] to antitumor [25,26] and anti-HIV [27][28][29][30] agents, to analogs [26,31] of the experimental anticancer drug (±)-1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OCH 3 , 1) [32] and platelet activating factor (PAF) [16].…”

“…The chemistry of pyrophosphate-linked sulfur-containing lipids also encompasses some anti-HIV nucleoside conjugates [27]. Linkage of (±)-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol 3-phosphate (17f) to nucleoside 5 -monophosphoromorpholidates by established protocols [43,45] afforded conjugates 20-22f [27].…”

Nucleic Acid Based Fluorinated Derivatives: New Tools for Biomedical Applications

“…Of particular interest is the design of hybrid amphiphilic nucleolipids featuring a bi-functionality based on the combination of nucleic acids and lipids [7][8][9][10][11][12][13][14][15]. Interestingly, different bottom-up approaches involving nucleolipids have been used for the construction of nanostructures for different applications, including materials [16][17][18] and biomedical devices [19][20][21]. In parallel to nucleolipid derivatives, the combination of nucleobase units with fluorocarbon…”