Liang Yuzeng, Narayanasamy Janarthanan, Rapp Kim L, Schinazi Raymond F, Chu Chung K
The University of Georgia College of Pharmacy, Athens, GA, USA.
Antivir Chem Chemother. 2006;17(6):321-9. doi: 10.1177/095632020601700602.
The synthesis, characterization, anti-HIV activity and cytotoxicity of dendrimers of (-)-beta-D-(2R, 4R)-dioxolane-thymine (DOT) and polyethylene glycol (PEG)-DOT conjugates are described. Dendrimers in this study were polyamidoamine (PAMAM) generation 2.0, 3.0, 5.0 and 6.0, along with 8.0-branched PEG with a molecular weight of 40 kDa. DOT was attached to PAMAM dendrimers or branched PEG via ester or phosphafte groups. Size exclusion chromatography was used to purify the dendrimers and PEG conjugates, which were characterized by NMR and MALDI-TOF mass spectrometry. The synthesized PAMAM dendrimers and PEG conjugates were evaluated for anti-HIV activity against HIV-1LAI in primary human peripheral blood mononuclear cells (PBMCs) and cytotoxicity in PBMCs, CEM and Vero cells. PAMAM dendrimers of DOT with ester linkages and particularly phosphate linkers showed an increase in anti-HIV potency in comparison with DOT alone (140- and 56-fold, respectively). Unfortunately, the PAMAM dendrimers also exhibited increased cytotoxicity. Anti-HIV activity of PEG-DOT conjugates was found to be lower than that of DOT.
描述了(-)-β-D-(2R, 4R)-二氧戊环胸腺嘧啶（DOT）树枝状聚合物以及聚乙二醇（PEG）-DOT共轭物的合成、表征、抗HIV活性和细胞毒性。本研究中的树枝状聚合物为第2.0、3.0、5.0和6.0代聚酰胺-胺（PAMAM），以及分子量为40 kDa的8.0分支PEG。DOT通过酯基或磷酸酯基连接到PAMAM树枝状聚合物或分支PEG上。采用尺寸排阻色谱法纯化树枝状聚合物和PEG共轭物，并用核磁共振（NMR）和基质辅助激光解吸电离飞行时间质谱（MALDI-TOF）对其进行表征。对合成的PAMAM树枝状聚合物和PEG共轭物在原代人外周血单核细胞（PBMC）中抗HIV-1LAI的活性以及在PBMC、CEM和Vero细胞中的细胞毒性进行了评估。带有酯键尤其是磷酸酯连接基的DOT的PAMAM树枝状聚合物与单独的DOT相比，抗HIV效力有所提高（分别提高了140倍和56倍）。不幸的是，PAMAM树枝状聚合物的细胞毒性也有所增加。发现PEG-DOT共轭物的抗HIV活性低于DOT。
