Conformational Analysis of Dehydrodidemnin B (Aplidine) by NMR Spectroscopy and Molecular Mechanics/Dynamics Calculations

• Published in: Journal of organic chemistry 2001-06, Vol.66 (13), p.4580-4584
• Main Authors: Cárdenas, Francisco, Thormann, Michael, Feliz, Miguel, Caba, Josep-Maria, Lloyd-Williams, Paul, Giralt, Ernest
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Computer Simulation; Depsipeptides; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Peptides, Cyclic - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo010123h

Dehydrodidemnin B (DDB or aplidine), a potent antitumoral natural product currently in phase II clinical trials, exists as an approximately 1:1 mixture 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-Pro8 terminal amide bond of the molecule's side chain. The same technique also indicates that the overall three-dimensional structures of both the cis and trans isomers of DDB are similar despite the conformational change. Molecular dynamics simulations with different implicit and explicit solvent models show that the ensembles of three-dimensional structures produced are indeed similar for both the cis and trans isomers. These studies also show that 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 the molecule's side chain and the Thr6 residue situated at the junction betwen the macrocycle and the molecule's side chain. Nevertheless, each conformational isomer forms this hydrogen bond using a different pyruvyl carbonyl group:  CO2 in the case of the cis isomer and CO1 in the case of the trans isomer.