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Design,Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents
Authors:Ziad Omran  Chris P Guise  Linwei Chen  Cyril Rauch  Ashraf N Abdalla  Omeima Abdullah  Ikhlas A Sindi  Peter M Fischer  Jeff B Smaill  Adam V Patterson  Yuxiu Liu  Qingmin Wang
Abstract:Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.
Keywords:phenanthroindolizidine  antofine  tylophorine  hypoxia  prodrugs  solid tumors
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