Proceedings book download - 5Z.com

Fig. 2. Secondary structure of heterodetictriazolyl cyclo-nonapeptides in DMSO/H2O80:20 v/v obatined by molecular dynamicsstudies. The intensity of bars is proportionalto the number of obtained conformers.MD studies were carried out in explicit solvent(DMSO/H2O 80:20 v/v) at room temperature for10ns using NMR low energy structures as startingpoint. The MD results (Figure 2) confirm theFig. 1. Short and medium range conformational stability of selected NMRconnectivities of compounds I-VIII, in structures for all cyclopeptides during theDMSO/water (80:20, v/v).simulations. The MD results confirm theconformational stability of selected NMRstructures for all cyclopeptides during the simulations. The obtained data show thatcyclopeptides V and VII are stabilized in the favourite conformation for the target interaction butonly compound V preserve this correct stabilization during all simulation time.To understand if the triazole was a coauthor in the correct conformational stabilization ofcycloeptides V and VII, radial distribution function (RDF) analysis were carried out (data notshown). The interactions of triazole ring with Ser4 and Gln6 respectively were evaluated. TheRDf results show that the interaction between Ser4 side chain and triazole is favourite when thetriazole nitrogens are oriented toward the C-term segment (compounds II VI and VIII). Thisinteraction gives an unfavourable contribution to the stabilization of the cyclopeptides II, VI, VIIsecondary structure. The RDf analysis shows that the interaction between Gln6 sidechain andtriazole ring is favourite in cyclopeptides V and VII, where the triazole nitrogens are orientedtoward the N-terminal region of cyclopeptides This interaction gives a favourable contribution tothe stabilization of the cyclopeptides V and VII in bturn I secondary structure.As previously mentioned we have recently reported a comprehensive conformationalanalysis employing CD, NMR and molecular dynamics of cyclopeptides I, II, V, VI, VII [1]. Wecompared the data presently reported, derived from NMR and MD analysis in DMSO/water,with the data in HFA/water. Interestingly all the data agree that that cyclo-nonapeptides (III-VI)in which the [1,2,3]triazolyl is flanked by a total of 5 or 6 methylenes nicely accommodate a-helical structures and reproduce very closely the helical structure stabilized by the analogouscyclo-nonapeptide in which Lys13 and Asp17 are bridged by the isosteric lactam.The agreement between data in HFA/water and DMSO/water as well as the conformationalstability in the dynamic calculation constitute strong evidence that the conformationalpreferences of tryazolil containing cyclopeptides are not affected by the solvent, but derive fromintrinsic chemical-physical properties of the cyclopeptides characterized by different size of thedisubstituted-[1,2,3]triazolyl-containing bridge, the location and the orientation of the[1,2,3]triazolyl moiety within the bridge.References1. Scrima, M., et al. Eur. J. Org. Chem. 3, 446-457 (2010).221