Cheong Jae Eun, Zaffagni Michela, Chung Ivy, Xu Yingjie, Wang Yiqiang, Jernigan Finith E, Zetter Bruce R, Sun Lijun
Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Eur J Med Chem. 2018 Jan 20;144:372-385. doi: 10.1016/j.ejmech.2017.11.037. Epub 2017 Dec 14.
Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC: 0.9-3.8 μM). Compound 18 achieved aqueous solubility of 361 μM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity.
转移是导致90%以上癌症死亡的原因，并且对大多数治疗反应不佳。对于晚期转移性癌症的治疗，迫切需要新的治疗方法。常用作抗蠕虫药的苯并咪唑氨基甲酸甲酯类药物已被认为具有抗癌活性，但其水溶性差且不适用于向播散性癌症进行全身给药，阻碍了相关进展。我们合成并表征了含氧杂环丁烷或胺基的新型苯并咪唑的抗癌活性，以提高其溶解度。其中，新型氧杂环丁烷基取代化合物18对多种癌细胞类型（包括前列腺癌、肺癌和卵巢癌）表现出显著的细胞毒性，对高侵袭性癌细胞系具有较强活性（IC：0.9 - 3.8 μM）。化合物18的水溶性达到361 μM。在高度转移性人类前列腺癌的小鼠异种移植模型中，化合物18（30 mg/kg）显著抑制已形成肿瘤的生长（T/C：0.36），且无明显毒性。
