Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-crystal Structure

Quinazolinone-based anticancer agents
were designed, decorated
with functional groups from a 2-methoxyestradiol-based microtubule
disruptor series, incorporating the aryl sulfamate motif of steroid
sulfatase (STS) inhibitors. The steroidal AB-ring system was mimicked,
favoring conformations with an N-2 substituent occupying
D-ring space. Evaluation against breast and prostate tumor cell lines
identified 7b with DU-145 antiproliferative activity
(GI50 300 nM). A preliminary structure–activity
relationship afforded compounds (e.g., 7j GI50 50 nM) with activity exceeding that of the parent. Both 7b and 7j inhibit tubulin assembly in vitro and colchicine
binding, and 7j was successfully co-crystallized with
the αβ-tubulin heterodimer as the first of its class,
its sulfamate group interacting positively at the colchicine binding
site. Microtubule destabilization by 7j is likely achieved
by preventing the curved-to-straight conformational transition in
αβ-tubulin. Quinazolinone sulfamates surprisingly showed
weak STS inhibition. Preliminary in vivo studies in a multiple myeloma
xenograft model for 7b showed oral activity, confirming
the promise of this template.

本研究设计了基于喹唑啉酮的抗癌剂，通过引入源自2-甲氧基雌二醇类微管干扰剂系列的官能团对其进行修饰，并整合了类固醇硫酸酯酶（STS）抑制剂的芳基氨磺酰基结构基序。研究模拟了甾体AB环体系，优选N-2取代基占据D环空间的优势构象。针对乳腺癌与前列腺癌细胞系的活性筛选显示，化合物7b对DU-145细胞具有抗增殖活性，其生长抑制半数浓度（GI50）为300 nM。初步构效关系研究获得了活性优于母核化合物的衍生物（如化合物7j，GI50为50 nM）。7b与7j均可在体外抑制微管蛋白组装及秋水仙碱结合活性；其中7j作为该类化合物中首个成功实现与αβ-微管蛋白异二聚体共结晶的分子，其氨磺酰基可在秋水仙碱结合位点产生正向相互作用。7j介导的微管解聚作用，可能通过阻断αβ-微管蛋白的弯曲-伸直构象转变实现。令人意外的是，喹唑啉酮类氨磺酰化合物仅表现出较弱的STS抑制活性。针对化合物7b的多发性骨髓瘤异种移植模型体内初步研究显示其具有口服活性，证实了该母核结构的研发潜力。