Receptor-bound conformation of cilengitide better represented by its solution-state structure than the solid-state structure.

The X-ray crystal and NMR spectroscopic structures of the peptide drug candidate Cilengitide (cyclo(RGDf(NMe)Val)) in various solvents are obtained and compared in addition to the integrin receptor bound conformation. The NMR-based solution structures exhibit conformations closely resembling the X-ray structure of Cilengitide bound to the head group of integrin αvß3. In contrast, the structure of pure Cilengitide recrystallized from methanol reveals a different conformation controlled by the lattice forces of the crystal packing. Molecular modeling studies of the various ligand structures docked to the αvß3 integrin revealed that utilization of the solid-state conformation of Cilengitide leads-unlike the solution-based structures-to a mismatch of the ligand-receptor interactions compared with the experimentally determined structure of the protein-ligand complex. Such discrepancies between solution and crystal conformations of ligands can be misleading during the structure-based lead optimization process and should thus be taken carefully into account in ligand orientated drug design.

Step-by-step synthesis of the endohedral stannaspherene [Ir@Sn12]3- via the capped cluster anion [Sn9Ir(cod)]3-.

The endohedral stannaspherene cluster anion [Ir@Sn(12)](3-) was synthesized in two steps. The reaction of K(4)Sn(9) with [IrCl(cod)](2) (cod: 1,5-cyclooctadienyl) in ethylenediamine (en) solution first yielded the [K(2,2,2-crypt)](+) salt (2,2,2-crypt: 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) of the capped cluster anion [Sn(9)Ir(cod)](3-). Subsequently, crystals of this compound were dissolved in en, followed by the addition of triphenylphosphine or 1,2-bis(diphenylphosphino)ethane and treatment at elevated temperatures. [Ir@Sn(12)](3-) was obtained and characterized as the [K(2,2,2-crypt)](+) salt. The isolation of [Sn(9)Ir(cod)](3-) as an intermediate product establishes that the formation of the stannaspherene [Ir@Sn(12)](3-) occurs through the oxidation of [Sn(9)Ir(cod)](3-). Among the structurally characterized tetrel cluster anions, [Ir@Sn(12)](3-) is a unique example of a stannaspherene, and one of the rare spherical clusters encapsulating a metal atom that is not a member of Group 10. Single-crystal structure determination shows that the novel Zintl ion cluster has nearly perfect icosahedral I(h) point symmetry.