Singh Ramendra K, Miazga Agnieszka, Dąbrowska Aleksandra, Lipniacki Andrzej, Piasek Andrzej, Kulikowski Tadeusz, Shugar David
Nucleic Acids & Antiviral Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad, India.
Antivir Chem Chemother. 2014 Dec 16;23(6):231-5. doi: 10.3851/IMP2679.
To improve in vitro antiviral activity and selectivity of stavudine (d4T), a range of its bi-functional prodrugs, 5'-O-myristoylated derivatives, have been synthesized.
Stavudine 5'-O-myristoylated esters were synthesized using modified Parang's procedure. The cytotoxicity and anti-HIV activity was evaluated in the established MT-4 cell line. The level of p24 protein in culture medium was assayed, and EC50 and EC90 values were determined.
Excellent anti-HIV activity was obtained for stavudine derivatives 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine with C10 and C11 alkyl chains bearing thioethyl- and azido- substituents. These prodrugs were more potent than the parent stavudine, as is clear from their EC50 values: 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine (R=CO(CH2)10SC2H5, EC50 0.06 μM), 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine (R=CO(CH2)11SC2H5, EC50 0.09 μM) and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine (R=CO(CH2)11N3, EC50 0.06 μM), while 50% cytotoxic concentration was >16.65 μM, >7.5 μM and >18.53 μM, respectively.
Overall data demonstrate that compounds 2',3'-didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro-2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12-azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine are very potent and selective anti-HIV agents and could be useful in treatment of HIV infections of the central nervous system.
为提高司他夫定（d4T）的体外抗病毒活性和选择性，已合成了一系列其双功能前药，即5'-O-肉豆蔻酰化衍生物。
采用改良的帕朗方法合成司他夫定5'-O-肉豆蔻酰化酯。在已建立的MT-4细胞系中评估细胞毒性和抗HIV活性。测定培养基中p24蛋白水平，并确定EC50和EC90值。
对于带有硫代乙基和叠氮基取代基的C10和C11烷基链的司他夫定衍生物2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（11-硫代乙基十一烷酰基）胸苷、2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（12-硫代乙基十二烷酰基）胸苷和5'-O-（12-叠氮基十二烷酰基）-2'，3'-二脱氢-2'，3'-二脱氧胸苷，获得了优异的抗HIV活性。这些前药比母体司他夫定更有效，从它们的EC50值可以清楚地看出：2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（11-硫代乙基十一烷酰基）胸苷（R = CO(CH2)10SC2H5，EC50 0.06 μM）、2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（12-硫代乙基十二烷酰基）胸苷（R = CO(CH2)11SC2H5，EC50 0.09 μM）和5'-O-（12-叠氮基十二烷酰基）-2'，3'-二脱氢-2'，3'-二脱氧胸苷（R = CO(CH2)11N3，EC50 0.06 μM），而50%细胞毒性浓度分别>16.65 μM、>7.5 μM和>18.53 μM。
总体数据表明，化合物2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（11-硫代乙基十一烷酰基）胸苷、2'，3'-二脱氢-2'，3'-二脱氧-5'-O-（12-硫代乙基十二烷酰基）胸苷和5'-O-（12-叠氮基十二烷酰基）-2'，3'-二脱氢-2'，3'-二脱氧胸苷是非常有效的选择性抗HIV药物，可用于治疗中枢神经系统的HIV感染。
