Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity

Yuqi Jiang; Jinning Hou; Xiaoyang Li; Yongxue Huang; Xuejian Wang; Jingde Wu; Jian Zhang; Wenfang Xu; Yingjie Zhang

doi:10.1016/j.bmc.2016.09.033

Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity

Bioorg Med Chem. 2016 Nov 15;24(22):5787-5795. doi: 10.1016/j.bmc.2016.09.033. Epub 2016 Sep 14.

Authors

Yuqi Jiang¹, Jinning Hou¹, Xiaoyang Li¹, Yongxue Huang², Xuejian Wang³, Jingde Wu¹, Jian Zhang³, Wenfang Xu¹, Yingjie Zhang⁴

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
² Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong 261061, PR China.
³ College of Pharmacy, Weifang Medical University, 261053 Weifang, Shandong, PR China.
⁴ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China. Electronic address: [email protected].

PMID: 27670098
DOI: 10.1016/j.bmc.2016.09.033

Abstract

Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro. The preliminary stability test of BC-A1 revealed that it could release gemcitabine in vitro. The in vivo anti-tumor results in liver cancer showed that at the same dosage, oral administration of BC-A1 was as potent as intraperitoneal administration of gemcitabine. This warranted the further research and development of the orally active prodrug BC-A1 because gemcitabine can not be orally administrated in clinic.

Keywords: Anti-angiogenesis; Anticancer; CD13 inhibitor; Gemcitabine (GEM); Ubenimex.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Angiogenesis Inhibitors / administration & dosage
Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aorta, Thoracic / drug effects
Apoptosis / drug effects
CD13 Antigens / antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation / drug effects
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives*
Deoxycytidine / chemistry
Deoxycytidine / pharmacology
Dose-Response Relationship, Drug
Drug Discovery*
Gemcitabine
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Leucine / administration & dosage
Leucine / analogs & derivatives*
Leucine / chemistry
Leucine / pharmacology
Molecular Structure
Rats
Structure-Activity Relationship
Swine

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Deoxycytidine
CD13 Antigens
Leucine
ubenimex
Gemcitabine