Pla Daniel, Francesch Andrés, Calvo Pilar, Cuevas Carmen, Aligué Rosa, Albericio Fernando, Alvarez Mercedes
Institute for Research in Biomedicine, Barcelona Science Park-University of Barcelona, and CIBER-BBN Networking Centre on Bioengineering, Biomaterials, and Nanomedicine, Baldiri Reixac 10, E-08028 Barcelona, Spain.
Bioconjug Chem. 2009 Jun;20(6):1100-11. doi: 10.1021/bc800503k.
Herein is reported the design and synthesis of poly(ethylene glycol) derivatives of Lamellarin D with the aim of modulating their physicochemical properties and improving the biological activity. Mono-, di-, and tri-PEG conjugates with improved solubility were obtained in 18-57% overall yields from the corresponding partially protected phenolic derivatives of Lamellarin D. Conjugates 1-9 were tested in a panel of three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon) to evaluate their cytotoxicity. Several compounds exhibited enhanced cellular internalization, and more than 85% of the derivatives showed a lower GI(50) than Lam-D. Furthermore, cell cycle arrest at G2 phase and apoptotic cell-death pathways were determined for Lamellarin D and these derivatives.
本文报道了海兔毒素D的聚乙二醇衍生物的设计与合成，目的是调节其物理化学性质并提高生物活性。从相应的部分保护的海兔毒素D酚类衍生物中以18 - 57%的总收率获得了具有改善溶解性的单、二和三PEG缀合物。在三种人类肿瘤细胞系（MDA - MB - 231乳腺癌细胞、A - 549肺癌细胞和HT - 29结肠癌细胞）中对缀合物1 - 9进行了测试，以评估它们的细胞毒性。几种化合物表现出增强的细胞内化作用，并且超过85%的衍生物显示出比海兔毒素D更低的半数生长抑制浓度（GI(50)）。此外，还确定了海兔毒素D及其这些衍生物在G2期的细胞周期阻滞和凋亡细胞死亡途径。
