B-Ring-Aryl Substituted Luotonin A Analogues with a New Binding Mode to the Topoisomerase 1-DNA Complex Show Enhanced Cytotoxic Activity
Figure 7
B-ring substitution improves hydrogen bonding to Arg364.
A. Overlay of luotonin A (3a) and compounds 3b–e at their binding sites, showing that the presence of the substituent at the C-14 position of ring B induces a rotation of the docking pose that leads to improved hydrogen bonding to Arg364 and hence to a better fit to the binding site. B. Docking of luotonin A showing the position of Asn352, which would interfere with any ring-B substituent. C. Docking of the B-phenyl substituted compound 3c, also showing the position of Asn352.