ABSTRACT
6-Methylpurine-beta-D-riboside (beta-D-MPR) has been synthesized by coupling 6-methylpurine and 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribose using conditions that produce the beta-D-anomer exclusively. The in vitro antitumor effects of beta-D-MPR and 6-methyl-purine-alpha-D-riboside (alpha-D-MPR) in five human tumor cell lines showed that beta-D-MPR was highly active (IC(50) values ranging from 6 to 34 nM). alpha-D-MPR, although less active than beta-D-MPR, also exhibited significant antitumor effects (IC50 values ranging from 1.47 to 4.83 microM).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Methylthioinosine/chemical synthesis , Methylthioinosine/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Methylthioinosine/chemistry , StereoisomerismABSTRACT
The N(6)-alkyladenosines and 2-methylthio-N(6)-alkyladenosines are the most common modified adenosine nucleosides, and transfer ribonucleic acids (tRNA) are particularly rich in these modified nucleosides. They are present at position 37 of the anticodon arm, and the contributions of these hypermodified nucleosides to codon-anticodon interactions as well as to translation are significant, although they are not fully understood. This unit describes a new chemical synthesis method for oligoribonucleotides containing N(6)-alkyladenosines and 2-methylthio-N(6)-alkyladenosines via postsynthetic modifications of precursor oligoribonucleotides. To obtain oligoribonucleotides containing N(6)-alkyladenosines, a precursor oligoribonucleotide carrying 6-methylthiopurine riboside residues was used, whereas for the synthesis of oligoribonucleotides containing 2-methylthio-N(6)-alkyladenosines, a precursor oligoribonucleotide carrying the 2-methylthio-6-chloropurine riboside was applied. This allowed synthesis of modified oligoribonucleotides containing naturally occurring modified nucleosides such as N(6)-isopentenyladenosine (i(6)A), N(6)-methyladenosine (m(6)A), 2-methylthio-N(6)-isopentenyladenosine (ms(2)i(6)A), and 2-methylthio-N(6)-methyladenosine (ms(2)m(6)A), as well as several unnaturally modified adenosine derivatives.
