Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents

我们开发新型微管解聚剂的努力，主要集中在天然的二酮基哌嗪，苯拉西汀，已经成功地在第二阶段临床试验中创造了一种高效的抗癌候选药物普利布林，它是一种导致肿瘤选择性血管崩溃的“血管干扰剂”。为了开发更有效的衍生物，已经从普利布林进行了合成孔径雷达的研究。二苯甲酮衍生物KPU-133的细胞毒性是普利布林的30倍，有望成为进一步药物开发的候选药物。此外，为了改善普利布林的低水溶性(&lt；0.1 mg/m L)，开发了一种高水溶的前药(6 mg/m L在水中)，通过独特的骨架从单乳素到DKP的转化来再生母药。另一方面，化学探针对微管蛋白结合部位的研究表明，普利布林衍生物可以在α-和β-微管蛋白的界面区域相互作用，并与秋水仙素结合部位部分重叠。

Our efforts to develop novel m icrotubule depolymerization agents, which was focused on a natural diketopiperazine, phenylahistin, have succeeded in creating a highly potent anticancer drug candidate "Plinabulin" in Phase II clinical trials as a "vascular disrupting agent", which induces tumor-selective vascular collapse. SAR study from plinabulin has been conducted to develop more potent derivatives. A benzophenone derivative KPU-133 exhibited a 30-times higher cytotoxicity than plinabulin and would be promising candidates for further drug development. Moreover, to improve the low water-solubility of plinabulin(<0.1 mg/mL), a highly water-soluble prodrug(6 mg/mL in water) was developed to regenerate the parent drug by a unique skeletal transformation from monolactim to DKP. On the other hand, investigation of the tubulin-binding site using chemical probes indicated that plinabulin derivatives could interact in the interfacial region of α-and β-tubulin, which partially overlaps with the colchicine-binding site.