Abstract
Psoralen-conjugated triplex-forming oligonucleotides (Ps-TFOs) have been used to induce
DNA mutations or to suppress gene expression through the formation of crosslinked
products with DNA in a sequence-specific manner. Psoralen can crosslink with DNA at
its furan-ring and/or pyrone-ring side, yielding either a monoadduct or diadduct (interstrand
crosslinking) product. The differences in the crosslinked structures of Ps-TFOs with
the target DNAs are closely related to the changes in the biological outcomes induced
by the Ps-TFOs. However, only a few reports have discussed the photocrosslinking properties
of Ps-TFOs. The photocrosslinking properties of Ps-TFOs with structurally diverse
psoralen derivatives remain elusive. Herein, we report the modular synthesis of novel
methyl-substituted psoralen N -hydroxysuccinimide (NHS) esters. By using these esters, the effect of the methyl
substituent of psoralen on the photocrosslinking of the corresponding Ps-TFOs was
examined. The amount of the diadduct product was significantly reduced in the presence
of methyl substituents at the C-3 and C-4 positions, while the total amount of photocrosslinking
product was maintained. This work demonstrates the possibility of controlling the
crosslinked product of Ps-TFOs by introducing methyl groups into psoralen: this ability
to manipulate the product is an important factor in the biological applications of
Ps-TFOs.
Key words psoralen - triplex-forming oligonucleotides - modular synthesis - substituent effect
- photocrosslinking - DNA crosslinking
