A Subtle Change in Linker Structure can Greatly Affect Cross-Linking Efficiency of a Quinone Methide Conjugate

The generality of delivering a bisquinone methide precursor to the major groove of DNA was tested with two naphthalimide conjugates differing in a single amide versus ester linkage. Both demonstrated an ability to cross-link duplex DNA. Although a difference in their efficiency was not anticipated, the amide-containing derivative consistently generated more cross-linking than its ester-containing analogue when tested with four different sequences of duplex DNA and one analogous RNA duplex. Both conjugates exhibited a specificity for a 5'-…GTGTGT…-3' sequence in the absence of the preferred target of 5'-GC and 5'-CG. A corresponding conjugate containing acridine in place of naphthalimide did not express a sequence specificity and cross-linked the test duplexes with an average efficiency similar to the median of that produced by the amide containing naphthalimide conjugate. With the plethora of naphthalimides available for cellular imaging and chemotherapy, quinone methide delivery may now be designed for many targets of choice. However, a variety of linkers should be surveyed to account for their surprising influence on cross-linking.