The synthesis and biological activities of oligodeoxynucleotides that are covalently linked to psoralen at their 5' ends

Four oligodeoxynucleotides (15-mers), designated 13 through 16, and the corresponding conjugates, designated 17 through 20, in which psoralen was covalently linked to the 5' end of each oligonucleotide were synthesized. Compounds 16 and 20 contained a sequence that was complementary to part of the first four codons and the upstream sequence close to the ribosome-binding site of c-Ha-ras mRNA. Compounds 16 and 20 inhibited the growth of cells that had been transformed by the c-Ha-ras plasmid, with accompanying suppression of the expression of the activated c-Ha-ras oncogene. The antisense oligonucleotides 16 and 20 also appeared to cause partial reversion of the major phenotypic characteristics of transformed cells, which included inhibition of anchorage-independent growth. Compound 20, which contained psoralen, was a more efficient inhibitor of the growth of transformed cells than compound 16 without psoralen, a result that suggests psoralen might have increased the ability of the oligodeoxynucleotides to enter the cells.