Design of B‐DNA cross‐linking and sequence‐reading molecules

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Abstract
We report the design of hybrid molecules to bind in the minor groove of B‐DNA, which combine DNA alkylating and cross‐linking ability for increased chemotherapeutic efficacy, with sequence specificity, to minimize side effects. Optimal linkage geometries have been determined for the synthesis of bis‐anthramycin and anthramycin‐netropsin hybrid molecules. Earlier studies on linked drugs have typically been based on molecular mechanics calculations. This work, in contrast, uses the observed crystal structures of a netropsin/DNA complex and a new anthramycin/DNA complex to determine the exact spacing between two individual drugs when bound in the minor groove of B‐DNA. Molecular linkers then are designed and tested between these two experimental positions, to form a chimeric or bis‐linked compound molecule. A linked anthramycin‐netropsin molecule has been designed specifically to target the polypurine tract second‐strand primer site of the reverse transcriptase of HIV‐1. © 1995 John Wiley & Sons, Inc.