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Synthesis and biological investigations of 5‐substituted pyrimidine nucleosides coupled to a dihydropyridine/pyridinium salt redox chemical delivery system
Author(s) -
Kumar Rakesh,
Wang L.,
Wiebe L.I.,
Knaus E.E.
Publication year - 2001
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200112)334:11<351::aid-ardp351>3.0.co;2-d
Subject(s) - chemistry , pyridinium , sodium dithionite , deoxyuridine , pyrimidine , lipophilicity , stereochemistry , biological activity , chemical synthesis , medicinal chemistry , morpholine , in vitro , organic chemistry , biochemistry , dna
The syntheses, antiviral activities, and partition coefficients ( P ) of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐coupled nucleosides are described. These novel compounds were designed in an effort to enhance the lipophilicity, and thereby the delivery to the CNS, without compromising the anti‐HSV‐1 activity of the parental nucleosides. We have previously reported the synthesis of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl) analogs of 5‐iodo‐( 5 ), 5‐vinyl‐( 6 ), and ( E )‐5‐(2‐iodovinyl)‐2'‐deoxyuridines ( 7 ). We now report the synthesis of 5‐iodo‐3'O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐5'‐O‐acetyl‐2'‐deoxyuridine ( 15 ) and 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐2'‐deoxyuridine ( 17 ). Quarternization of the 3'‐O‐(3‐pyridylcarbonyl) compounds ( 10,12 ) using iodomethane afforded the corresponding 1‐methyl pyridinium salts ( 13,14 ) which were reduced with sodium dithionite to yield the corresponding 3'‐O‐1‐methyl‐1,4‐dihy‐dropyridyl‐3‐carbonyl compounds ( 15,16 ). The deprotection of 3'‐O‐(1‐methyl‐1,4‐dihy‐dropyridyl‐3‐carbonyl)‐5'‐O‐ t ‐butyldimethylsilyl‐2'‐deoxyuridine ( 16 ) with Bu 4 N + F ‐ afforded 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐2'‐deoxyuridine ( 17 ). Compounds 5‐7 and 15 were evaluated for their antiviral activity in vitro against HSV‐1, HSV‐2, HCMV, and VZV, and were found to retain anti‐HSV‐1, HSV‐2 and VZV activity as compared to their parental nucleosides ( 1—3 ). In addition, the cellular toxicity of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐coupled compounds ( 5—7 and 15 ) was found to be lower than the parent nucleosides. The lipophilicity of compounds ( 5—7,15,17 ) are enhanced substantially, compared to the parent nucleosides, as indicated by an increase in corresponding P values (1‐octanol‐water) upon replacement of the C‐3' hydroxyl by 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl moiety.