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

Abstract

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.

Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion

“…Based on our previous experience with the known nitrones 9a – d , 9f [ 23 , 24 ], and 9g [ 25 ] as well as new nucleobase-derived mono-nitrone 9e , the bis-nitrones 9h , i were prepared following the reactions shown in Scheme 1 and Scheme 2 , respectively (Materials and Methods). Thus, the aldehydes of type I ( Scheme 1 ) and the bis-aldehydes 10 and 11 ( Scheme 2 ) were obtained directly from their respective nucleobase via mono- and dialkylation with bromoacetaldehyde diethyl acetal and subsequent acetal hydrolysis according to the literature protocol [ 26 ]. For the transformation of mono- and bis-aldehydes into the respective nitrones, 9a – g and 9h , i , the appropriate amounts of MeNHOH-HCl/Na 2 CO 3 were used (2 eq.…”

Synthesis of Propargylic Fluorides toward Carbo- and Heterocycles with Mono- and gem-Difluorinated Side Chains

“…9). 16 In the case of propargylic sulfides 23, electrochemical methods have been employed. Starting from aryl propargylic sulfides 22, anodic fluorination (with Et 3 N•xHF as the supporting electrolyte as well as the fluorine source) gave the targets 23 in low to moderate yields but these molecules proved to be unstable and could not be isolated in pure form.…”

Synthesis of Modified Purine Nucleosides and Related Compounds Mediated by Adenosine Deaminase (ADA) and Adenylate Deaminase (AMPDA)

“…[81][82][83] Adenine acyclonucleosides including compounds 70 and 71 ( Figure 10) are also substrates of ADA. [84][85][86][87] A few 9-[(hydroxyalkyl)phenyl]adenines 72-74 were synthesized and tested as substrates of ADA. 88 The time for quantitative enzymatic deamination of compounds 70-74 are shown in brackets in Figure 10.…”