title: Synthesis and investigation of N4-substituted cytarabine derivatives as prodrugs.
abstract: Esters of Cytarabine-N4-carboxylates 2a-i and succinamates 3a-f were synthesized as prodrugs of cytarabine (Ara-C) with the aim of developing improved derivatives for oral or parentral administration. At pH 2 series 2 showed relative higher stability than 3, while both series of esters revealed matched stability at pH 7. All esters were susceptible to enzymatic hydrolysis by rat plasma and liver homogenate with half lives ranged from 0.14 h to 12 d, and showed improved stability against cytidine deaminase. A parabolic relation was shown between Kobs of enzymatic hydrolysis and Vw. All compounds are more lipophilic than the parent drug, Ara-C.
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Egypt.
authors.forename: T A
authors.initials: TA
authors.lastname: Fadl
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: A F
authors.initials: AF
authors.lastname: Youssef
authors.forename: H H
authors.initials: HH
authors.lastname: Farag
authors.forename: F A
authors.initials: FA
authors.lastname: Omar
authors.forename: T
authors.initials: T
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D003564:Cytidine Deaminase / Q000378:metabolism; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet
chemical_list: D002021:Buffers; D011355:Prodrugs; D003561:Cytarabine; D003564:Cytidine Deaminase