期刊
MOLECULES
卷 26, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/molecules26113327
关键词
phenanthroindolizidine; antofine; tylophorine; hypoxia; prodrugs; solid tumors
资金
- King Abdulaziz City for Science and Technology (KACST) [13-MED2515-10, B-RES-2020-0028]
Phenanthroindolizidines are natural alkaloids with pronounced cytotoxicity against human cancerous cell lines, but are associated with neurotoxicity and loss of in vivo activity. By developing them as hypoxia-targeted prodrugs, their cytotoxicity can be increased while minimizing other side effects.
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.
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