Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates
Synthesis, antiviral and contraceptive activities of nucleoside-sodium cellulose sulfate acetate and succinate conjugates
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DOI：
10.1016/j.bmcl.2010.09.133
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发表时间：
2010-12-01
影响因子：
2.7
通讯作者：
Parang, Keykavous
中科院分区：
文献类型：
--
作者：
Agarwal, Hitesh K.;Kumar, Anil;Parang, Keykavous
纤维素硫酸钠（CS）显示避孕和HIV进入抑制特性，与核苷逆转录酶抑制剂（NRTI）（3 '-叠氮基-2'，3 '-双脱氧胸苷（AZT）、3'-氟-2 '，3'-双脱氧胸苷（FLT）或2 '，3'-双脱氧-3 '-硫代胞苷（3 TC））之间的化学缀合物被设计为同时提供避孕和抗HIV活性。两个接头，乙酸酯和琥珀酸酯，用于缀合核苷类似物与CS。含有硫酸-乙酸纤维素（CSA）的缀合物（e.例如，在一个实施例中，AZT-CSA和FLT-CSA）被发现比CS和其他缀合物（例如，例如，在一个实施例中，AZT-琥珀酸酯-CS和FLT-琥珀酸酯-CS）。纤维素上硫酸根和乙酸根基团的存在对于产生最大抗HIV活性至关重要。除了对野生型和多药耐药HIV-1显示出相同的效力外，AZT-CSA缀合物在动物模型中显示出显著的避孕活性，为基于这些组合的双活性化合物的设计和合成提供了初步的概念验证。(C)2010爱思唯尔有限公司保留所有权利。
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.