AIDS dementia: synthesis and properties of a derivative of 3'-azido-3'-deoxythymidine (AZT) that may become 'locked' in the central nervous system.
In an attempt to provide a derivative of 3'-azido-3'-deoxythymidine (AZT) which might be sequestered in the central nervous system and release AZT, the dihydropyridine ester 5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-deoxythymidine, was synthesized in a three step sequence. This material showed potent anti-HIV-1 activity in MT-4 cells most probably by hydrolysis to the parent nucleoside, AZT. This dihydropyridine derivative of AZT could be easily oxidized to a positively charged pyridinium derivative of AZT in rat brain cytosol. In turn the pyridinium form could be hydrolyzed, non-enzymatically, to AZT.
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Section on Biomedical Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892.
Kinjo
J
J
Lesiak
K
K
Balzarini
J
J
De Clercq
E
E
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000188:drug therapy; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003704:Dementia / Q000188:drug therapy* / Q000209:etiology; D004095:Dihydropyridines; D006678:HIV / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008980:Moloney murine sarcoma virus / Q000187:drug effects / Q000502:physiology; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives
D004095:Dihydropyridines; D004364:Pharmaceutical Preparations; D011355:Prodrugs; C056534:5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-azido-3'-deoxythymidine; D015215:Zidovudine; D013936:Thymidine