Synthesis of Novel N⁹-Substituted Purine Derivatives from Polymer Supported α-Amino Acids

Abstract

Solid-phase synthesis of purine derivatives bearing an α-amino acid motif in position 9 is described herein. Polymer supported amines were acylated with various Fmoc-α-amino acids and, after cleavage of the protecting group, arylation with 4,6-dichloro-5-nitropyrimidine or 2,4-dichloro-5-nitropyrimidine was performed. The second chlorine atom was replaced with various amines. Subsequent reduction of the nitro group, followed by reaction with aldehydes, afforded the purine scaffold. After cleavage from the polymer support, the target compounds were obtained in very good crude purity, good overall yields, and excellent enantiomeric purity. The anticancer activity of prepared compounds was tested in vitro against human cancer cell lines MCF7 and K562, and they were found to have mild, but clear dose-dependent effects.

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

“…Polymersupported α-amino acids 151 were used as the starting material. 48 The purine scaffold was accessed by the pyrimidine intermediates 154 cyclization with aldehydes (Scheme 24). The cyclization step was significantly accelerated by microwave heating (30 min vs 72 h for conventional heating).…”

“…Recently, the method for the preparation of similar derivatives was developed using the pyrimidine intermediates. Polymer-supported α-amino acids 151 were used as the starting material . The purine scaffold was accessed by the pyrimidine intermediates 154 cyclization with aldehydes (Scheme ).…”

“…For this purpose, he developed a new method for the C 8 bromination of immobilized purine intermediates 160 using a charge-transfer complex of bromine with lutidine in NMP (Scheme ). For the subsequent Suzuki or Stille coupling of the bromoderivative 161 , application of Pd­(OAc) 2 and Cu 2 O catalysis was identified as the most suitable procedure . Purines with primary alkylamino substituents at their C 2 and C 6 positions gave better coupling results than those bearing secondary amino functions .…”

1H and 13C NMR spectral data of p‐nitrobenzenesulfonamides and dansylsulfonamides derived from N‐alkylated o‐(purinemethyl)anilines

“…In recent years, purine bases have been the subject of extensive research that led to the discovery of thousands of biological active compounds, including antineoplastic ones. [1][2][3][4][5][6] We synthesized a novel series of alkylated purines (1)(2)(3)(4)(5)(6)(7)(8)(9) with notable in vitro anti-proliferative activities, low toxicity and systemic distribution after oral administration in vivo. [1] The design of these compounds was based on the modifications of acyclic O,N-acetals, previously described by our research group as anti-proliferative agents.…”

“…In recent years, purine bases have been the subject of extensive research that led to the discovery of thousands of biological active compounds, including antineoplastic ones . We synthesized a novel series of alkylated purines ( 1‐9 ) with notable in vitro anti‐proliferative activities, low toxicity and systemic distribution after oral administration in vivo .…”