Ene Reaction of Nitrosocarbonyl Mesitylene with the Cinnamyl Alcohol: Metabolic Activity and Apoptosis of the Synthetized 6-Chloropurine N,O-Nucleoside Analogues

Abstract

Nitrosocarbonyl mesitylene intermediate undergoes an ene reaction with cinnamyl alcohol affording the corresponding 5-hydroxy-isoxazolidine in fair yields. The synthesized 5-acetoxy-isoxazolidine serves as synthon for the preparation of 6-chloropurine N,O-nucleoside analogues, according to the Vorbrüggen reaction. The compounds were evaluated for their metabolic and apoptotic activity, and their structure–activity relationship is discussed.

N,O‐Nucleoside Analogues: Metabolic and Apoptotic Activity

“…The isoxazolidine 12 , prepared according to reported procedure, was derivatized with the commercially available purine, 6‐chloropurine and benzoimidazole rings by adapting the standard protocol for the insertion of heterobases on isoxazolidine rings . The acetylated isoxazolidine 12 was added under nitrogen atmosphere at r.t. to a solution of 2.2 equiv.…”

“…We then performed the functionalization of the isoxazolidine 9 with the commercially available uracil U and thymine T by adapting the standard protocol for the insertion of heterobases on isoxazolidine rings . The acetylated isoxazolidine 9 was added under nitrogen atmosphere at r.t. to a solution of uracil U or thymine T (2.2 equiv.)…”

“…The purine nucleoside analogues 11 a – d were isolated in fair yields (range 22–36 %). On the basis of previous observations, the reaction gave a mixture of four isomeric products where the purine ring can be linked at the isoxazolidine moiety through the N7 and/or N9 nitrogen atoms.…”

“…In a previous work, we investigated the metabolic and induced cell death by apoptosis of a family of 6‐chloropurine N,O ‐nucleoside analogues derived from the ene reaction of the cinnamyl alcohol and the mesityl nitrosocarbonyl intermediate 1 M . Among the various 6‐chloropurine regio‐ and stereoisomers obtained through the Vorbrüggen derivatization of the 5‐acetoxy‐isoxazolidine 5 , it was demonstrated that compound 6 a , showing the 6‐chloropurine ring cis ‐related to the phenyl ring of the isoxazolidine moiety, was more cytotoxic than that the corresponding 6 b in the pro‐apoptotic, metabolic and cytotoxic activities, tested on the human monocytoid U937 and the lymphoblastoid MOLT‐3 cell lines (Scheme ).…”

“…At the heterobases level, both the groups contain the 6‐chloropurine ring for comparison with the data already known and pyrimidine‐ and purine‐types bases are also included. The biological assays will furnish further details on the SAR for these types of isoxazoline analogues.…”