Diastereomers of Dibromo-7-epi-10-deacetylcephalomannine:Crowded and Cytotoxic Taxanes Exhibit Halogen Bonds

摘要

The diastereomers of dibromo-7-epi-10-deacetylcephalomannine (6 and 7) have been isolated and characterized.Cytotoxicity and microtubule assembly assays demonstrate that cephalomannine analogue 6 possesses a potency profile very similar to that of Taxol,while isomer 7 is slightly less active.Solid state,solution,and tubulin-bound conformations of the two diastereomers were probed by using X-ray crystallography,2-D NMR experiments in conjunction with the NAMFIS analysis,and the Glide docking protocol.In the crystal,isomer 7 exhibits an intermolecular halogen bond that may contribute to self-assembly.Neither crystal structure appears in the NAMFIS solution analysis,but both diastereomers are represented in solution by a T-shaped Taxol conformer.Glide docking demonstrates the latter to best fill the tubulin binding pocket,as has been shown for the parent Taxol drug.Each model of the bound complexes for 6 and 7 presents a single well-defined halogen bond from one of the ligand's bromines to Glu22 or Asp26 near the N-terminus of beta-tubulin,respectively.This first report of a halogen bond between taxanes and tubulin may prove useful in guiding the design and synthesis of other microtubule-stabilizing agents with a similar capacity.