problems for DNA repair systems (Section 8.11). Tomaymycinhas been shown to induce greater confor-
mational changes, namely helix bendingand associated narrowing of the minor groove, than does
anthramycin. It thus appears that sequence-dependent conformational flexibility may be an important fac-
tor in determining the selectivity for DNA sequence binding of P[1,4]Bs.^51
Richard Dickerson has solved a 2.3Å X-ray crystal structure of anthramycinbonded to a duplex
decamer d(C-C-A-A-C-G-T-T-G-G). One drug molecule sits within the minor groove at each end of the
helix, covalently bound through its C-11 position to the N-2 amine of the penultimate guanine of the chain.^52
The configuration at C-11 is (S) for both residues (Figure 8.25). With this configuration, the natural twist
of the anthramycin molecule matches the twist of the minor groove whereas a C-11(R) drug would fit only
into a left-handed helix. The acrylamide tail attached to the five-membered ring extends back along the
minor groove toward the center of the helix, binding in a manner reminiscent of netropsin or distamycin.
The origin of anthramycin specificity for three successive purines appears to arise not from specific hydro-
gen bonds but from the low twist angles adopted by purine–purine steps in a B-DNA helix (Section 2.2.4).
312 Chapter 8
Figure 8.25 Crystal structure of a covalent DNA-drug adduct: anthramycin bound to C-C-A-A-C-G-T-T-G-G and
a molecular explanation of specificity^52 (Adapted from a figure kindly provided by M. Kopka.)