DESIGN OF B-DNA CROSS-LINKING AND SEQUENCE-READING MOLECULES

We report the design of hybrid molecules to bind in the minor groove o f B-DNA, which combine DNA alkylating and cross-linking ability for in creased chemotherapeutic efficacy, with sequence specificity, to minim ize side effects. Optimal linkage geometries have been determined for the synthesis of bis-anthramycin and anthramycin-netropsin hybrid mole cules. Earlier studies on linked drugs have typically been based on mo lecular mechanics calculations. This work, in contrast, uses the obser ved crystal structures of a netropsin/DNA complex and a new anthramyci n/DNA complex to determine the exact spacing between two individual dr ugs when bound in the minor groove of B-DNA. Molecular linkers then ar e designed and tested between these two experimental positions, to for m a chimeric or bis-linked compound molecule. A linked anthramycin-net ropsin molecule has been designed specifically to target the polypurin e tract second-strand primer site of the reverse transcriptase of HIV- 1. (C) 1995 John Wiley & Sons, Inc.