Source:http://linkedlifedata.com/resource/pubmed/id/10814087
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
2000-10-27
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pubmed:abstractText |
Synthesis of spirocyclic analogues of 2'-deoxyadenosine and 2'-deoxyguanosine (12a-15a and 12b-15b) is described. Rhodium-catalyzed reaction of ethyl diazoacetate with methylenecyclopropane 19, obtained from 2-bromo-2-bromomethylcyclopropane 17 via debromination (16), reduction (18), and acetylation (19), gave a mixture of all four isomeric spiropentanes 20a-20d. Hydrolysis afforded hydroxy carboxylic acids 21a-21d. Acetylation of separated proximal + medial-syn isomers 21a + 21b and medial anti + distal isomers 21c + 21d furnished acetates 22a + 22b and 22c + 22d. Curtius rearrangement effected by diphenylphosphoryl azide in tert-butyl alcohol performed separately with mixtures 22a + 22b and 22c + 22d led to BOC-amino spiropentanes 23a + 23b and 23c + 23d. After deacetylation all isomers 24a-24d were separated and deprotected to give aminospiropentane hydrochlorides 25a-25d. Free bases were of limited stability. The heterocyclic moieties were introduced into individual isomers 25a-25d via 6-chloropurine derivatives 26a-26d or 30a-30d. Ammonolysis of 26a-26d furnished the adenine isomeric series 12a-15a, whereas guanine derivatives 12b-15b were obtained by hydrolysis of 30a-30d with formic acid. The isomeric assignments followed from IR spectra of BOC-aminospiropentanes 24a-24d and NMR spectra of 12a-15a including NOE and (H,H) COSY. The proximal and medial-syn isomers 12a and 12b were modest inhibitors of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in culture, whereas the medial-anti isomer 12c was a substrate for adenosine deaminase. The distal isomer 15b was an anti-EBV agent. The medial-syn phosphoralaninate 34 was an effective inhibitor of HCMV replication in vitro. It was also active against herpes simplex virus type 1 (HSV-1), varicella zoster virus (VZV), human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), and EBV with a varying degree of cytotoxicity.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyadenosines,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyguanosine,
http://linkedlifedata.com/resource/pubmed/chemical/Pentanes,
http://linkedlifedata.com/resource/pubmed/chemical/Spiro Compounds
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-3263
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
10
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pubmed:volume |
65
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1280-90
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:10814087-Acetylation,
pubmed-meshheading:10814087-Antiviral Agents,
pubmed-meshheading:10814087-Cytomegalovirus,
pubmed-meshheading:10814087-Deoxyadenosines,
pubmed-meshheading:10814087-Deoxyguanosine,
pubmed-meshheading:10814087-Herpesvirus 4, Human,
pubmed-meshheading:10814087-Humans,
pubmed-meshheading:10814087-Hydrolysis,
pubmed-meshheading:10814087-Magnetic Resonance Spectroscopy,
pubmed-meshheading:10814087-Pentanes,
pubmed-meshheading:10814087-Spectrophotometry, Infrared,
pubmed-meshheading:10814087-Spiro Compounds,
pubmed-meshheading:10814087-Stereoisomerism
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pubmed:year |
2000
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pubmed:articleTitle |
Spiropentane mimics of nucleosides: analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, isomeric assignment, and biological activity.
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pubmed:affiliation |
Department of Chemistry, Experimental and Clinical Chemotherapy Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, Michigan 48201-1379, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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