title: Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-Amino prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine.
abstract: A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds are intended to be more lipophilic than the currently approved anti-HIV drugs for better blood-brain barrier penetration. Subsequent adenosine deaminase (ADA)-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI). The new compounds, synthesized from the corresponding 6-chloro analog, include F-ddN which contain methylamino, ethylamino, dimethylamino, hydroxylamino, methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in the 6-position. The 6-nitro analog was isolated as an unexpected product during the preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity, the ethylamino and dimethylamino compounds are ca. 100 times more lipophilic than ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results in hydrolysis of the group in the 6-position rather than glycosylic bond cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rates which vary from slightly slower (NO2, 1.7x) to much slower (NHEt, 5000x) than F-ddA. The 6-dimethylamino analog is the only compound which possesses anti-HIV activity (ED50 18 microM) without ADA hydrolysis. With the exception of the two inactive alkoxyamino compounds, the other prodrugs exhibited cellular protection in the HIV-1/PHA-PBM system with IC50 potencies of 7-40 microM.
authors.affiliation: Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Driscoll
authors.forename: M A
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: H
authors.initials: H
authors.lastname: Ford
authors.forename: J A
authors.initials: JA
authors.lastname: Kelley
authors.forename: J S
authors.initials: JS
authors.lastname: Roth
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D016049:Didanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D012995:Solubility
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; C083218:2'-fluoro-2',3'-dideoxyinosine; D000243:Adenosine Deaminase; D016049:Didanosine