Narayanasamy Janarthanan, Pullagurla Manik R, Sharon Ashoke, Wang Jianing, Schinazi Raymond F, Chu Chung K
The University of Georgia College of Pharmacy, Athens, GA 30602, United States.
Antiviral Res. 2007 Sep;75(3):198-209. doi: 10.1016/j.antiviral.2007.03.005. Epub 2007 Mar 30.
Prodrugs of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD), organic salts of DAPD, 5'-L-valyl DAPD and N-1 substituted (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) have been synthesized with the objective of finding molecules which might be superior to DAPD and DXG in solubility as well as pharmacologic profiles. Synthesized prodrugs were evaluated for anti-HIV activity against HIV-1(LAI) in primary human lymphocytes (PBM cells) as well as their cytotoxicity in PBM, CEM and Vero cells. DAPD prodrugs, modified at the C6 position of the purine ring, demonstrated several folds of enhanced anti-HIV activity in comparison to the parent compound DAPD without increasing the toxicity. The presence of alkyl amino groups at the C6 position of the purine ring increased the antiviral potency several folds, and the most potent compound (-)-beta-D-(2R,4R)-1,3-dioxolane-2-amino-6-aminoethyl purine (8) was 17 times more potent than that of DAPD. 5'-L-Valyl DAPD 20 and organic acid salts 21-24 also exhibited enhanced anti-HIV activity in comparison to DAPD, while DXG prodrugs 16 and 17 exhibited lower potency than that of DXG or DAPD.
合成了（-）-β-D-（2R，4R）-1，3-二氧戊环-2，6-二氨基嘌呤（DAPD）的前药、DAPD的有机盐、5'-L-缬氨酰-DAPD以及N-1取代的（-）-β-D-（2R，4R）-1，3-二氧戊环鸟苷（DXG），目的是找到在溶解性和药理学特性方面可能优于DAPD和DXG的分子。对合成的前药在原代人淋巴细胞（外周血单核细胞[PBM]细胞）中针对HIV-1（LAI）的抗HIV活性以及它们在外周血单核细胞、CEM和Vero细胞中的细胞毒性进行了评估。在嘌呤环的C6位修饰的DAPD前药与母体化合物DAPD相比，抗HIV活性提高了数倍，且未增加毒性。嘌呤环C6位存在烷基氨基使抗病毒效力提高了数倍，最有效的化合物（-）-β-D-（2R，4R）-1，3-二氧戊环-2-氨基-6-氨乙基嘌呤（8）的效力比DAPD高17倍。与DAPD相比，5'-L-缬氨酰-DAPD 20和有机酸盐21-24也表现出增强的抗HIV活性，而DXG前药16和17的效力低于DXG或DAPD。
