Peng Yingyuan, Shi Zhixian, Liang Yuru, Ding Kuiling, Wang Yang
School of Pharmacy, Fudan University, Shanghai, 201203, China.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
Eur J Med Chem. 2022 Jun 5;236:114344. doi: 10.1016/j.ejmech.2022.114344. Epub 2022 Apr 5.
In response to the long-term potential toxicity concerns of tubulin destabilizer, an enzyme-responsive prodrug therapy for triple-negative breast cancer was developed based on the different β-glucuronidase levels between tumor and normal tissues in this study. All the prodrugs synthesized herein showed remarkable stability in phosphate buffer and bovine serum solution, among which 17a was found to be more susceptible to enzymatic cleavage. 17a exhibited excellent selectivity between the in vitro antiproliferative activities against β-glucuronidase-pretreated and -untreated cancer cells (IC (+Enz) = 8.9-15.7 nM, IC (-Enz) > 50 μM), along with favorable liver microsomal metabolic stability and improved aqueous solubility. Furthermore, as a candidate prodrug 17a showed potent antitumor efficacy in MDA-MB-231 xenograft mouse model without causing perceptible injury to organs. Importantly, 17a exhibited superior safety profiles with higher LD value and no perceivable cardiotoxicity, which was a major dose-limiting adverse effect for the parent compound 1. These salient toxicity-reduced effects of 17a would merit further in-depth assessment of this compound for preclinical therapeutic usages.
鉴于微管蛋白稳定剂存在长期潜在毒性问题，本研究基于肿瘤组织与正常组织中β-葡萄糖醛酸酶水平的差异，开发了一种用于三阴性乳腺癌的酶响应前药疗法。本文合成的所有前药在磷酸盐缓冲液和牛血清溶液中均表现出显著的稳定性，其中17a被发现更易受酶切作用影响。17a在对β-葡萄糖醛酸酶预处理和未处理的癌细胞的体外抗增殖活性之间表现出优异的选择性（IC(+Enz)=8.9 - 15.7 nM，IC(-Enz)>50 μM），同时具有良好的肝微粒体代谢稳定性和改善的水溶性。此外，作为候选前药，17a在MDA-MB-231异种移植小鼠模型中显示出强大的抗肿瘤功效，且未对器官造成明显损伤。重要的是，17a表现出卓越的安全性，具有更高的半数致死量值且无明显心脏毒性，而心脏毒性是母体化合物1的主要剂量限制性不良反应。17a这些显著的毒性降低作用值得对该化合物进行进一步深入的临床前治疗用途评估。
