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.

中文翻译：

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基于喹唑啉酮的抗癌药：合成，抗增殖SAR，抗微管蛋白活性和微管蛋白共晶体结构

设计了基于喹唑啉酮的抗癌剂，并修饰了基于2-甲氧基雌二醇的微管破坏剂系列的官能团，并结合了甾族硫酸酯酶（STS）抑制剂的芳基氨基磺酸酯基序。模拟甾体AB-环系统，有利于具有占据D-环空间的N -2取代基的构象。针对乳腺癌和前列腺肿瘤细胞系的评估确定了7b具有DU-145抗增殖活性（GI ₅₀ 300 nM）。初步的结构-活性关系提供了活性超过母体的化合物（例如7j GI ₅₀ 50 nM）。无论7B和7J抑制微管蛋白在体外的组装和秋水仙碱的结合，并成功地将7j与αβ-微管蛋白异二聚体共结晶，这是其首个类别，其氨基磺酸盐基团在秋水仙碱的结合位点呈正相互作用。7j引起的微管失稳可能是通过防止α-微管蛋白从弯曲到笔直的构象转变来实现的。氨基磺酸喹唑啉酮令人惊讶地显示出弱的STS抑制作用。在多发性骨髓瘤7b异种移植模型中的初步体内研究显示了口服活性，证实了该模板的前景。