Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates.
Chemical conjugates between sodium cellulose sulfate (CS), displaying contraceptive and HIV-entry inhibiting properties, and nucleoside reverse transcriptase inhibitors (NRTIs) (3'-azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), or 2',3'-dideoxy-3'-thiacytidine (3TC)) were designed to simultaneously provide contraceptive and anti-HIV activity. Two linkers, acetate and succinate, were used to conjugate the nucleoside analogs with CS. The conjugates containing cellulose sulfate-acetate (CSA) (e.g., AZT-CSA and FLT-CSA) were found to be more potent than CS and other conjugates (e.g., AZT-succinate-CS, and FLT-succinate-CS). The presence of both sulfate and the acetate groups on cellulose were critical for generating maximum anti-HIV activity. In addition to showing equal potency against wild-type and multidrug resistant HIV-1, the AZT-CSA conjugate displayed significant contraceptive activity in an animal model, providing the initial proof-of-concept for the design and synthesis of dual-activity compounds based on these combinations.
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Hitesh K
HK
Agarwal
Anil
A
Kumar
Gustavo F
GF
Doncel
Keykavous
K
Parang
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D003270:Contraceptive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004359:Drug Therapy, Combination / Q000379:methods*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D023421:Models, Animal; D009705:Nucleosides / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013386:Succinates / Q000737:chemistry*
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D003270:Contraceptive Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D013386:Succinates; D002482:Cellulose; C020254:cellulose sulfate; D054303:HIV Reverse Transcriptase