Conformational analysis of dehydrodidemnin B (Aplidine) by NMR spectroscopy and molecular mechanics/dynamics calculations

Dehydrodidemnin B (DDB or aplidine), a potent antitumoral natural product c urrently in phase II clinical trials, exists as an approximately 1:1 mixtur e of two slowly interconverting conformations. These are sufficiently long- lived so as to allow their resolution by HPLC. NMR spectroscopy shows that this phenomenon is a consequence of restricted rotation about the Pyr-Pro(8 ) terminal amide bond of the molecule's side chain. The same technique also indicates that the overall three-dimensional structures of both the cis an d trans isomers of DDB are similar despite the conformational change. Molec ular dynamics simulations with different implicit and explicit solvent mode ls show that the ensembles of three-dimensional structures produced are ind eed similar for both the cis and trans isomers. These studies also show tha t hydrogen bonding patterns in both isomers are alike and that each one is stabilized by a hydrogen bond between the pyruvyl unit at the terminus of t he molecule's side chain and the Thr(6) residue situated at the junction be tween the macrocycle and the molecule's side chain. Nevertheless, each conf ormational isomer forms this hydrogen bond using a different pyruvyl carbon yl group: CO2 in the case of the cis isomer and CO1 in the case of the tran s isomer.