Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Agarwal, Hitesh K.¹  Kumar, Anil¹  Doncel, Gustavo F.²  Parang, Keykavous¹ 

[1] Univ Rhode Isl, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA

[2] Eastern Virginia Med Sch, Dept Obstet & Gynecol, CONRAD, Norfolk, VA 23507 USA

关键词: Sodium cellulose sulfate;    Nucleoside;    Anti-HIV;    Cellulose acetate;    AZT;    FLT;    3TC;    Contraceptive;   

DOI  :  10.1016/j.bmcl.2010.09.133

来源: Elsevier

【 摘 要 】

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. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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