Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents
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
Affiliations
Ziad Omran
Department of Pharmaceutical Sciences, Pharmacy Department, Batterjee Medical College, Jeddah 21442, Saudi Arabia
Chris P. Guise
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Linwei Chen
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
Cyril Rauch
School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington LE12 5RD, UK
Ashraf N. Abdalla
College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Omeima Abdullah
College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Ikhlas A. Sindi
Department of Biology, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Peter M. Fischer
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK
Jeff B. Smaill
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Adam V. Patterson
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Yuxiu Liu
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
Qingmin Wang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
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.
