2. Academic Validation
  3. Synthesis and anticancer activity of novel water soluble benzimidazole carbamates

Synthesis and anticancer activity of novel water soluble benzimidazole carbamates

  • Eur J Med Chem. 2018 Jan 20:144:372-385. doi: 10.1016/j.ejmech.2017.11.037.
Jae Eun Cheong 1,  Michela Zaffagni 2,  Ivy Chung 3,  Yingjie Xu 2,  Yiqiang Wang 1,  Finith E Jernigan 1,  Bruce R Zetter 4,  Lijun Sun 5
Affiliations

Affiliations

  • 1 Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 3 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
  • 4 Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: bruce.zetter@childrens.harvard.edu.
  • 5 Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: lsun1@bidmc.harvard.edu.
PMID: 29288939 DOI: 10.1016/j.ejmech.2017.11.037
Abstract

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 (IC50: 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.

Keywords

Anticancer activity; Benzimidazole; Oxetane; Solubility.

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