VanNatta Jennifer M, Carlson Graham J, Niu Haichan, Bai Ruoli, Wanniarachchi Hashini I, Schuetze Regan, Trawick Mary Lynn, Hamel Ernest, Mason Ralph P, Pinney Kevin G
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, Texas 76798-7348, United States.
Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
ACS Med Chem Lett. 2025 May 26;16(6):1098-1107. doi: 10.1021/acsmedchemlett.5c00129. eCollection 2025 Jun 12.
Colchicine site inhibitors of tubulin polymerization function as antiproliferative anticancer agents, with certain inhibitors demonstrating a dual mechanism of action as tumor-selective vascular disrupting agents (VDAs). Our previous studies yielded potent benzosuberene-based colchicine site inhibitors of tubulin polymerization. To expand structure-activity correlations, the seven-membered fused ring and the pendant ring were modified to generate a series of new compounds, 11 being strong inhibitors (IC ≤ 5 μM) of tubulin polymerization. Structural modifications introduced a second benzylic olefin and, separately, a nitrogen atom to the fused seven-membered ring, along with conversion to unique tetracyclic fused ring systems. Two of the active inhibitors were synthetically converted to corresponding phosphate prodrug salts to increase aqueous solubility for studies. In a preliminary study of VDA efficacy, these prodrugs caused blood flow disruption in mice, as revealed by bioluminescence imaging with histological confirmation. The most effective analogues from this series offer promise as cancer therapeutic agents.
微管蛋白聚合的秋水仙碱位点抑制剂可作为抗增殖抗癌药物，某些抑制剂还表现出作为肿瘤选择性血管破坏剂（VDA）的双重作用机制。我们之前的研究得到了有效的基于苯并环庚烯的微管蛋白聚合秋水仙碱位点抑制剂。为了扩展构效关系，对七元稠环和侧环进行了修饰，以生成一系列新化合物，其中11种是微管蛋白聚合的强抑制剂（IC≤5μM）。结构修饰引入了第二个苄基烯烃，并分别在稠合七元环中引入了一个氮原子，同时转化为独特的四环稠环系统。两种活性抑制剂被合成转化为相应的磷酸前药盐，以提高其水溶性用于研究。在VDA疗效的初步研究中，这些前药导致小鼠血流中断，生物发光成像结合组织学证实了这一点。该系列中最有效的类似物有望成为癌症治疗药物。
