药物学论文讲解创新.pptVIP

Tubulin polymerization inhibitor 1 Introduction 1.1 Microtubule A dynamic cellular compartment in both neoplastic and normalcells Structure Never hydrolyze or exchange May hydrolyze or exchange Target Structure Functions of microtubules Formation and Maintenance of Cell Shape Intracellular transport 1.2 Design The most potent tubulin polymerization inhibitor 2a, IC50 values 0.2 to 0.4 μm, but 10- to 100-fold less active than 1 2a, R1=3,4,5-(OCH3)3, R2=pyrrolidin-1-yl Ref. 1 Experentia, 45(1989), 209–211; Ref. 2 Eur. J. Med. Chem., 46(2011), 6015-6024. 2 Chemistry Ref. Tetrahedron, 65(2009), 2982–2988. Ref. Organic Letters, 4(2002), 979–981. 3 Biological Results and Discussion 3.1 In Vitro Antiproliferative Activities 人宫颈癌细胞 人结肠癌细胞 乳腺癌细胞 急性T细胞白血病 人幼粒白血病细胞 人肺癌细胞 3.2 Effect of Compound 3b on Multidrug Resistant Cells 人肺癌细胞 人大肠癌细胞 白血病细胞 3.3 In Vivo Antitumor Activity of Compound 3b 3.4 Molecular Modeling Common Molecular Docking Software Dock Auto Dock Surflex Glide Gold Molegro Virtual Docker Plants Proposed binding mode of 3b in the colchicine site of β-tubulin 赖氨酸 甲硫氨酸 酪氨酸 天冬氨酸 缬氨酸 半胱氨酸 A tight hydrophobic pocket Hydrogen bond Van der Waals 4 Conclusions