Direct, solid phase assembly of dihydropyrroloindole peptides with conjugated oligonucleotides.
A new controlled pore glass (CPG) support is described that allows for the direct synthesis of oligonucleotide derivatives carrying a minor groove binding (MGB) agent at the 3'-terminus. The MGB consisted of three repeating 1,2-dihydro-3H-pyrrolo[2,3-e]indole-7-carboxylate (DPI) subunits. The DPI trimer (DPI3) was prepared directly on the CPG support using repeated addition of the DPI subunit. The subunit was protected at the N-3-position with tert-butyloxycarbonyl residue and activated at the 7-carboxy residue by esterification with the 2,3,5,6-tetrafluorophenyl group. A linker, which provided the starting point for oligonucleotide synthesis, was introduced by reaction of the terminal N-3 with p-nitrophenyl 4-[bis(4-methoxyphenyl)phenylmethoxy]butyrate. When used as a support for oligonucleotide synthesis, this modified CPG gave the desired 3'-DPI3-octathymidylate [(dTp)8-DPI3] conjugate in good yield. This conjugate formed hyperstabilized complexes with complementary polyribo- (Tmax = 35 degrees C) and polydeoxyriboadenylic (Tmax = 69 degrees C) acids. In contrast to the N-carbamoyl derivative reported earlier by us, it demonstrated higher cooperativity of melting transitions.
Lukhtanov
E A
EA
Epoch Pharmaceuticals, Inc., Bothell, Washington 98021, USA.
Kutyavin
I V
IV
Meyer
R B
RB
D005898:Glass; D007211:Indoles / Q000737:chemistry*; D009841:Oligonucleotides / Q000138:chemical synthesis*; D011758:Pyrroles / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
D007211:Indoles; D009841:Oligonucleotides; D011758:Pyrroles; C013231:pyrroline