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Conjugation of N ‐(3‐(9‐Ethynyl‐6 H ‐indolo[2,3‐ b ]quinoxalin‐6‐yl)propyl)‐2,2,2‐trifluoroacetamide Intercalator to a Triplex Forming Oligonucleotide, a Three‐Way Junction, and a G‐Quadruplex
Author(s) -
Osman Amany M. A.,
Pedersen Erik B.
Publication year - 2019
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201900554
Subject(s) - chemistry , phosphoramidite , monomer , oligonucleotide , quinoxaline , stereochemistry , moiety , alkylation , nucleobase , medicinal chemistry , dna , organic chemistry , polymer , biochemistry , catalysis
A new intercalating nucleic acid monomer Z comprising an 3‐(9‐((4‐oxyphenyl)ethynyl)‐6 H ‐indolo[2,3‐b]quinoxalin‐6‐yl)propan‐1‐amine moiety was synthesized. When Z was inserted into triplex forming oligonucleotides, high thermal stability was observed for its corresponding Hoogsteen‐type triplexes. Three‐way junction (TWJ) was studied by targeting a DNA strand to the foot of a DNA or an RNA hairpin. When Z was inserted into the DNA strand, this resulted in the highest increase of thermal melting ever reported for a TWJ modified by insertion of an intercalator into the junction site. Experiments with mismatches confirmed formation of the TWJ. Improvements in stability of a G‐quadruplex were achieved by insertion of the monomer Z by replacement of one of the nucleotides in the TGT loop. The first steps in the synthesis of the monomer Z were condensation of 5‐iodoisatin with o‐phenylene diamine under reflux in acetic acid and subsequent alkylation reaction with 2‐(3‐bromopropyl)isoindoline‐1,3‐dione followed by suitable reduction led to 3‐(9‐Iodo‐6 H ‐indolo[2,3‐b]quinoxalin‐6‐yl)propan‐1‐amine which in turn was treated with ethyl trifluoroacetate with formation of 2,2,2‐trifluoro‐ N ‐(3‐(9‐iodo‐6 H ‐indolo[2,3‐b]quinoxalin‐6‐yl)propyl)acetamide. This compound was reacted by Sonogashira coupling conditions to give the diol which was converted into the DMT‐protected phosphoramidite, which in turn was used to incorporate the monomer Z into oligonucleotides.