Dal Pozzo Alma, Ni Minghong, Muzi Laura, de Castiglione Roberto, Mondelli Rosanna, Mazzini Stefania, Penco Sergio, Pisano Claudio, Castorina Massimo, Giannini Giuseppe
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milano, Italy.
J Med Chem. 2006 Mar 9;49(5):1808-17. doi: 10.1021/jm0511334.
A series of six arginine-glycine-aspartate (RGD) cyclopeptide analogues containing a C(alpha)-di- or trifluoromethylamino acid (alpha-Dfm or alpha-TfmAaa) at different positions of the ring were synthesized. All peptides were obtained in two diastereomeric forms, which were separated by HPLC. In vitro biological tests of the new cyclopeptides P were carried out in comparison with their corresponding cyclopeptides R lacking the alpha-fluoromethyl group. Five out of the six compounds P-I (containing (S)-alpha-Tfm-Aaa) showed activities in the nanomolar range, while the P-II compounds (containing (R)-alpha-Tfm-Aaa) were much less active or totally inactive. Only cyclo[RGDf-(S)-alphaTfmV] (P1-I) was found to be significantly more active than its model compound cyclo(RGDfV) (R1). The three-dimensional structure in water and DMSO was determined by NMR techniques and molecular dynamics (MD) calculations, but it was not possible to highlight significant differences in the backbone conformation of the peptides examined. Significant interproton distances, derived from nuclear Overhauser effect (NOE) experiments, were used to determine the absolute configuration of the side chains.
合成了一系列六种精氨酸-甘氨酸-天冬氨酸（RGD）环肽类似物，这些类似物在环的不同位置含有一个α-二氟或三氟甲基氨基酸（α-Dfm或α-TfmAaa）。所有肽均以两种非对映体形式获得，并通过高效液相色谱法分离。将新的环肽P与其相应的不含α-氟甲基基团的环肽R进行了体外生物学测试。六种化合物P-I中的五种（含有（S）-α-Tfm-Aaa）显示出纳摩尔范围内的活性，而P-II化合物（含有（R）-α-Tfm-Aaa）活性低得多或完全无活性。仅发现环[RGDf-（S）-αTfmV]（P1-I）比其模型化合物环（RGDfV）（R1）活性明显更高。通过核磁共振技术和分子动力学（MD）计算确定了在水和二甲亚砜中的三维结构，但无法突出所研究肽的主链构象的显著差异。源自核Overhauser效应（NOE）实验的显著质子间距离用于确定侧链的绝对构型。
