Discovery of a novel chimeric ubenimex-gemcitabine with potent oral antitumor activity.
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.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
Yuqi
Y
Jiang
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
Jinning
J
Hou
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
Xiaoyang
X
Li
Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong 261061, PR China.
Yongxue
Y
Huang
College of Pharmacy, Weifang Medical University, 261053 Weifang, Shandong, PR China.
Xuejian
X
Wang
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
Jingde
J
Wu
College of Pharmacy, Weifang Medical University, 261053 Weifang, Shandong, PR China.
Jian
J
Zhang
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China.
Wenfang
W
Xu
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji'nan, Shandong, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
Yingjie
Y
Zhang
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D000093542:Gemcitabine
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex; D000093542:Gemcitabine
Anti-angiogenesis; Anticancer; CD13 inhibitor; Gemcitabine (GEM); Ubenimex