Zipping up the strands

In their search for new anticancer drugs medicinal chemists are developing compounds that inhibit DNA replication and cell proliferation.

Some molecules achieve this by forming crosslinks between complementary strands of DNA, known as DNA interstrand crosslinking (DNA ISC). Harold Kohn and Sang Hyup Lee at the University of North Carolina, US, have prepared a dimeric mitomycin designed to undergo DNA ISC easily when activated under nucleophilic and reducing conditions.

The two mitomycin units are bridged by a cyclic dithiane unit. Cleaving the disulfide bond resulted in a thiol species that activated the tethered mitomycin units towards attack by nucleophiles. Disrupting the conjugated backbone enabled DNA adduction at two distal mitomycin sites and crosslinking occurred with guanine base pairs on two DNA strands. Adding phosphines accelerated disulfide cleavage and generated higher levels of the crosslinked DNA adduct than with other mitomycins that are proven anticancer agents.

Rachel Hopper