Studies on the Antisense Oligonucleotide Conjugate

Four oligonucleotides (15 mer) 13–16 and their conjugates 17–20 in which psoralen was covalently linked to 5′ end were synthesized. Compounds 16 and 20 contain the sequence which is complementary to the sense strand covering the first four codons and the upstream sequence close to the ribosome binding site of c-Ha-ras mRNA. It was found that compounds 16 and 20 inhibited the growth of cells that had been transformed by the c-Ha- ras plasmid activated c-Ha- ras oncogene. Compound 20 that carried psoralen was more efficient in inhibiting the growth of transformed cells than compound 16 without psoralen, suggesting that the psoralen might have increased permeability of oligodeoxynucleotides. A model experiment of duplex formation was pertinent to the idea that the inhibitory effect was caused by RNase H activity.