Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents

Molecules

Chris P. Guise¹  Jeff B. Smaill¹  Adam V. Patterson¹  Ashraf N. Abdalla²  Omeima Abdullah²  Ikhlas A. Sindi³  Ziad Omran⁴  Peter M. Fischer⁵  Cyril Rauch⁶  Yuxiu Liu⁷  Qingmin Wang⁷  Linwei Chen⁷ 

[1] Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;Department of Biology, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia;Department of Pharmaceutical Sciences, Pharmacy Department, Batterjee Medical College, Jeddah 21442, Saudi Arabia;School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK;School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington LE12 5RD, UK;State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China;

关键词: phenanthroindolizidine;    antofine;    tylophorine;    hypoxia;    prodrugs;    solid tumors;   

DOI  :  10.3390/molecules26113327

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown