Abstract

BACKGROUND:

Bladder cancer is one of the most common types of cancer diagnosed each year, and more than half of patients have non-muscle invasive bladder cancer (NMIBC). The standard of care for patients with high-grade NMIBC is Bacillus Calmette-Guerin (BCG). Unfortunately, multiple BCG shortages have limited access to this treatment. Available alternatives using intravesical administration of chemotherapy have some efficacy, but lack prospective validation and long-term outcomes. Development of novel intravesical therapies may provide more active alternatives to BCG for patients with high-grade NMIBC.

OBJECTIVE:

To develop an optimal imidazolium salt for the intravesical treatment of NMIBC and determine preliminary in vitro activity of anthraquinone-substituted imidazolium salts.

METHODS:

The development of the anthraquinone-substituted imidazolium salts was undertaken in an attempt to increase the potency of this class of compounds by incorporating the quinone functional group observed in the chemotherapeutics doxorubicin, valrubicin, and mitomycin. All compounds were characterized by ¹H and ¹³C NMR spectroscopy and infrared spectroscopy. Furthermore, these imidazolium salts were tested for in vitro cytotoxicity by the Developmental Therapeutics Program (DTP) on the NCI-60 human tumor cell line screening. Additional in vitro testing was performed against diverse bladder cancer cell lines (RT112, TCCSUP, J82, and UMUC13) using CellTiter-Glo® assays and colony-forming assays.

RESULTS:

The NCI-60 cell line screening indicated that compound 7 had the highest activity and was concluded to be the optimal compound for further study. Using CellTiter-Glo® assays on bladder cancer cell lines, 50% growth inhibitory concentration (IC₅₀) values were determined to range from 32–50μM after an exposure of 1 h, for compound 7. Further evaluation of the compound by colony-forming assays showed the complete inhibition of growth at 10 days post a 100μM dose of compound 7 for 1 h.

CONCLUSIONS:

The most active lipophilic anthraquinone imidazolium salt, compound 7, could be a viable treatment for non-muscle invasive bladder cancer as it exhibits a cell-killing effect at a 1 h time period and completely inhibits cancer regrowth in colony-forming assays.

中文翻译：

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蒽醌取代的咪唑鎓盐的合成，表征和生物学活性用于治疗膀胱癌

摘要

背景：

膀胱癌是每年诊断出的最常见的癌症之一，并且一半以上的患者患有非肌肉浸润性膀胱癌（NMIBC）。患有高级NMIBC的患者的护理标准是卡介苗芽孢杆菌（BCG）。不幸的是，多次卡介苗短缺限制了这种治疗的机会。使用膀胱内化疗的可用替代方法具有一定疗效，但缺乏前瞻性验证和长期结果。对于高级别NMIBC患者，新型膀胱内疗法的开发可能为BCG提供更有效的替代方法。

目的：

为NMIBC的膀胱内治疗开发一种最佳的咪唑鎓盐，并确定蒽醌取代的咪唑鎓盐的初步体外活性。

方法：

尝试开发蒽醌取代的咪唑鎓盐，以通过结合在化学疗法中观察到的阿霉素，阿霉素和丝裂霉素中的醌官能团来增强此类化合物的效力。所有化合物均通过¹ H和¹³ C NMR光谱和红外光谱表征。此外，在NCI-60人肿瘤细胞系筛选中，通过发育治疗计划（DTP）测试了这些咪唑鎓盐的体外细胞毒性。使用CellTiter-Glo®分析法和集落形成分析法对多种膀胱癌细胞系（RT112，TCCSUP，J82和UMUC13）进行了额外的体外测试。

结果：

NCI-60细胞系筛选表明化合物7具有最高活性，并被认为是进一步研究的最佳化合物。对膀胱癌细胞系使用的CellTiter-Glo®底测定，50％生长抑制浓度（IC ₅₀）值被确定为范围从32-50 μ 1个小时的曝光后男，为化合物7。通过集落形成测定法的化合物的进一步评价表明生长的第10天完全抑制发布100 μ化合物的M剂量7 1个小时。

结论：

最具活性的亲脂性蒽醌咪唑盐，化合物7，对于非肌肉浸润性膀胱癌可能是一种可行的治疗方法，因为它在1小时内显示出细胞杀伤作用，并在菌落形成试验中完全抑制了癌症的再生。