Herdman Christine A, Strecker Tracy E, Tanpure Rajendra P, Chen Zhi, Winters Alex, Gerberich Jeni, Liu Li, Hamel Ernest, Mason Ralph P, Chaplin David J, Trawick Mary Lynn, Pinney Kevin G
Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
Prognostic Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9058, United States.
Medchemcomm. 2016 Dec 1;7(12):2418-2427. doi: 10.1039/C6MD00459H. Epub 2016 Sep 22.
The natural products colchicine and combretastatin A-4 () have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of (referred to as ) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as ), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC < 5 μM), and benzocyclooctene phenol was comparable to in terms of potency. The analogous indene-based compound also functioned as an inhibitor of tubulin polymerization (IC = 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue , and it was converted to its water-soluble prodrug salt to assess its potential as a VDA. Preliminary studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with , a clinically relevant VDA, were carried out as a positive control.
天然产物秋水仙碱和康普瑞他汀A-4（）激发了人们设计和合成结构相关类似物及衍生化合物作为微管蛋白聚合抑制剂的灵感。发现（称为）的水溶性磷酸前药盐能够对肿瘤相关血管造成深刻且选择性的损伤，这为开发一种利用微管蛋白聚合小分子抑制剂（其也作为血管破坏剂（VDA））的癌症治疗新方法铺平了道路。将与秋水仙碱和相关的显著结构特征相结合，导致设计和合成了多种稠合芳基 - 环烷基和芳基 - 杂环化合物，它们作为微管蛋白聚合抑制剂发挥作用。这些化合物中突出的是一种苯并环庚烯类似物（称为），它对人癌细胞系表现出亚纳摩尔的细胞毒性，并且（当作为水溶性前药盐给药时）在小鼠模型中作为VDA发挥作用。结构活性关系的考虑导致对苯并环辛基[6,8稠合]和茚[6,5稠合]环系统进行评估。制备了四种苯并环辛烯和四种茚类似物并进行生物学评估。三种苯并环辛烯类似物作为微管蛋白聚合抑制剂具有活性（IC<5μM），并且苯并环辛烯苯酚在效力方面与相当。类似的基于茚的化合物也作为微管蛋白聚合抑制剂发挥作用（IC = 11μM），效力降低。该组中最有效的微管蛋白聚合抑制剂是苯并环辛烯类似物，并且将其转化为其水溶性前药盐以评估其作为VDA的潜力。初步研究在SCID小鼠模型中使用MCF7 - luc - GFP - mCherry乳腺肿瘤，结果表明用（120mg / kg）治疗导致显著的血管关闭，给药后4小时的生物发光成像证明了这一点，并且在24小时和48小时时这种效果持续存在。作为阳性对照，进行了与临床相关的VDA的同期研究。
