Unsaturated Acyclic Analogs of 2'-Deoxyadenosine and Thymidine Containing Fluorine: Synthesis and Biological Activity

• Published in: Journal of medicinal chemistry 1995-03, Vol.38 (6), p.875-882
• Main Authors: Xu, Ze-Qi, Qiu, Yao-Ling, Chokekijchai, Sudhichai, Mitsuya, Hiroaki, Zemlicka, Jiri
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cattle; Deoxyadenosines - chemical synthesis; Deoxyadenosines - pharmacology; HIV - drug effects; HIV - physiology; Humans; Hydrocarbons, Fluorinated - chemical synthesis; Hydrocarbons, Fluorinated - pharmacology; Isomerism; Leukemia L1210 - drug therapy; Medical sciences; Mice; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; Thymidine - analogs & derivatives; Thymidine - pharmacology; Virus Replication - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00006a004

The syntheses and biological activities of fluorobutynol 11 and (E)- and (Z)-fluorobutenols 8a,d and 9a,d are described. Alkylation of adenine with bromofluorobutyne 13a afforded intermediate 14 which was converted to fluorobutynol 11. Aldehyde 16a and (carbethoxyfluoromethyl)-triphenylphosphonium bromide furnished (E)- and (Z)-fluorobutenoates 19a and 20a accompanied by regioisomer 21a. A similar reaction of compound 16d afforded Z- and E-esters 19d and 20d. Reduction of the mixture of 19a and 20a with DIBALH gave (E)- and (Z)-fluoroalkenols 8a and 9a. Similarly, the Z-ester 19d gave (Z)-fluoroalkenol 9d. Both 19d and 20d were reduced with NaBH4 to give (Z)- and (E)-fluoroalkenols 9d and 8d. Hydrogenation of 19a and 20a afforded fluoro ester 23. A similar reduction of 8a and 9a led to fluoro alcohol 24 and the defluorinated product 25 which were separated by chromatography on a Bio-Rad AG 1-X2 (OH-) column. (Z)-Fluorobutenol 9a is a substrate for adenosine deaminase, whereas the E-isomer 8a is inert toward the enzyme. By contrast, analogue 8a inhibited the replication and cytopathic effect of HIV-1 in ATH8 cells with an IC50 of approximately 100 microM, but the Z-isomer 9a was inactive. This effect was accompanied by 36% cytotoxicity at 100 microM. Compounds 11 and 8d inhibited the growth of murine leukemia L1210 culture with IC50 = 89 and 60 microM, respectively.