{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:47:20Z","timestamp":1786560440540,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004919","name":"King Abdulaziz City for Science and Technology","doi-asserted-by":"publisher","award":["13-MED2515-10"],"award-info":[{"award-number":["13-MED2515-10"]}],"id":[{"id":"10.13039\/501100004919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2013brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.<\/jats:p>","DOI":"10.3390\/molecules26113327","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T15:58:44Z","timestamp":1622563124000},"page":"3327","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Design, Synthesis and In-Vitro Biological Evaluation of Antofine and Tylophorine Prodrugs as Hypoxia-Targeted Anticancer Agents"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-4035","authenticated-orcid":false,"given":"Ziad","family":"Omran","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Pharmacy Department, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris P.","family":"Guise","sequence":"additional","affiliation":[{"name":"Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linwei","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Rauch","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington LE12 5RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-9319","authenticated-orcid":false,"given":"Ashraf N.","family":"Abdalla","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1296-3045","authenticated-orcid":false,"given":"Omeima","family":"Abdullah","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikhlas A.","family":"Sindi","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5866-9271","authenticated-orcid":false,"given":"Peter M.","family":"Fischer","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff B.","family":"Smaill","sequence":"additional","affiliation":[{"name":"Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5138-1227","authenticated-orcid":false,"given":"Adam V.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiu","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingmin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2174\/1568009043332989","article-title":"Novel approaches for targeted cancer therapy","volume":"4","author":"Guillemard","year":"2004","journal-title":"Curr. 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