title: Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates.
abstract: A series of methoxy poly(ethylene glycol)-succinyl-5'-O-zidovudine conjugates (mPEG-succinyl-AZT) with different molecular weight (M(w): 750 Da, 2, 5 or 10 kDa) of mPEG were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy, and matrix-assisted laser desorption/ionization time of flight mass (MALDI TOF MS) spectrometry analysis. All conjugates showed good stability in vitro release experiments, and good anti-HIV activity and low cytotoxicity in MT-4 cells, in which, mPEG(750)-succinyl-AZT exhibited good inhibition to wild-type viruses (strains IIIB and ROD) with EC(50) values of 0.11 and 0.090 μmol/L, respectively, and it showed no cytotoxicity up to 110 μmol/L. Oral pharmacokinetic study in rats showed the half-life time (T(1/2)) of all conjugates are prolonged compared to free AZT. Especially, mPEG(750)-succinyl-AZT displayed a ~2.3-fold prolonged half-life and approximately 224% increased bioavailability of AZT.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Jingde
authors.initials: J
authors.lastname: Wu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.forename: Yu
authors.initials: Y
authors.lastname: Chang
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D060326:Chemistry Techniques, Synthetic; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013057:Spectrum Analysis; D015215:Zidovudine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D011092:Polyethylene Glycols; D015215:Zidovudine