Synthesis and Antiviral Activities of 8-Alkynyl-, 8-Alkenyl-, and 8-Alkyl-2'-deoxyadenosine Analogs

Abstract

Palladium-catalyzed cross-coupling of 8-bromo-2'-deoxyadenosine with terminal alkynes in the presence of copper(I) iodide in dimethylformamide resulted in a series of 8-(1-alkyn-1-yl)-2'-deoxyadenosines. Hydrogenation of alkynyl derivatives over 10% Pd/C under atmospheric pressure gave 8-n-alkyl analogues in nearly quantitative yields. On partial saturation of heptynyl, pentynyl, and propynyl derivatives over Lindlar catalyst, the corresponding cis-olefins were obtained along with minor amounts of trans isomers. Of the analogues tested, the following showed some activity, i.e. they were found to be active at concentrations that were at least 3-fold lower than the cytotoxic concentrations: the 8-heptynyl derivative against vaccinia virus (VV), vesicular stomatitis virus (VSV), cytomegalovirus (CMV), and respiratory syncytial virus (RSV); the 8-propyl derivative against varicella-zoster virus (VZV) and CMV; the 8-pentyl derivative against CMV; the 8-heptyl derivative against VV, CMV, RSV, and influenza A; and the 8-heptenyl derivative against VV, RSV, and influenza A. The unsubstituted 2'-deoxyadenosine did not show any antiviral effect, except against RSV. Except for 8-propyl-dA, the antivirally active dA analogues were rather inhibitory to the growth of human embryonic lung cells. The most cytotoxic was the 8-ethynyl derivative.

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

“…Suzuki coupling of purines: Purines, the core bases of the DNA and RNA nucleotide building blocks adenine and guanine, represent an important class of biologically active compounds and are used as antiviral [83][84][85][86][87] or anticancer agents. [85,[88][89][90][91][92][93] Suzuki couplings have been used to introduce various substituted aryl groups into purine systems.…”

Synthesis, Antiplatelet Aggregation Activity Evaluation and 3D‐QSAR of a Series of Novel 6‐Alkylamino(Alkoxyl)‐2‐Propylthio‐8‐Azapurine Nucleosides

“…As shown in Scheme 4, we first combined 2-propylthio-6-chloro-8-azapurine (5) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (6) in the presence of the Lewis acid SnCl 4 to gain the intermediate 9-[(2′,3′,5′-tri-O-benzoyl)-β-D-ribofuranosyl]-2-propylthio-6-chloro-8-azapurine (7). However, through experimentation, we discovered that this method yields three isomers (7′) in which the N 7 , N 8 , and N 9 positions of the purine ring were substituted.…”

“…In recent years, AstraZeneca modified the C-2, N 6 and ribose, or cyclopentane substituents of the 8-azapurine scaffold and obtained a series of N 6 -alkyl(aryl)-2-alkyl(aryl)thio-8-azapurine nucleoside derivatives [11,12]. AstraZeneca evaluated these derivatives as antiplatelet agents and found that AR-C78511 and AZD6140 ( Fig.…”

Heck Reactions of 6‐ and 2‐Halopurines

“…[9] Several methodologies have been used for the preparation of alkenylpurines. 6-Styrylpurine was first prepared by condensation of 6-methylpurine with benzaldehyde in the presence of HCl.[10] Another, more general, synthetic approach to 6-alkenylpurines, is based on Wittig reactions between 9-protected (purin-6-yl)methylene-triphenyl-λ 5 -phosphanes (Wittig reagents) and aldehydes or ketones.[11]Cyclic 6-alkenyloxypurines have been prepared by intramolecular cyclization of 6-(hydroxyalkyn-1-yl)purines, [12] while 6-enaminopurines are accessible by addition of amines to 6-alkynylpurines.[13] Partial hydrogenation of 2-alkynyl- [14] and 8-alkynylpurines [15] to give the corresponding alkenes has also been reported. Hydrogenation of 6-alkynylpurines to 6-alkenylpurines was reported to proceed satisfactorily only with 9-unprotected bases, with overhydrogenation taking place otherwise.…”