Synthesis of phenanthroindolizidine alkaloids and evaluation of their antitumor activities and toxicities

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 19; pp. 5978 - 5981
• Main Authors: Ikeda, Takashi, Yaegashi, Takashi, Matsuzaki, Takeshi, Yamazaki, Ryuta, Hashimoto, Syusuke, Sawada, Seigo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.10.2011; Elsevier
• Subjects: Alkaloids; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Alkaloids - toxicity; Animals; anticarcinogenic activity; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Antitumor activity; Antitumor agents; Biological and medical sciences; Cell Line, Tumor; chemical structure; Cytotoxicity; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; General aspects; HT29 Cells; Humans; Hydroxides - chemistry; Hydroxides - metabolism; Indolizines - chemical synthesis; Indolizines - chemistry; Indolizines - pharmacology; Indolizines - toxicity; Male; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Phenanthroindolizidine alkaloid; Phenanthrolines - chemical synthesis; Phenanthrolines - chemistry; Phenanthrolines - pharmacology; Phenanthrolines - toxicity; Stereoisomerism; Structure-Activity Relationship; Toxicity; Xenograft Model Antitumor Assays; Toxicity; Phenanthroindolizidine alkaloid; Antitumor activity; Antineoplastic agent; Human; Solid tumor; Rodentia; Cytotoxicity; In vitro; In vivo; Vertebrata; Alkaloid; Mammalia; Cell line; Structure activity relation; Mouse; Animal; Phenols; Colon; Chemical synthesis; Tumor cell
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.120

We previously reported that phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem. To address this problem, new phenanthroindolizidine derivatives were synthesized and their antitumor activities and toxicities were evaluated. This study describes the relationship between the chemical structures, antitumor activities, and toxicities of these phenanthroindolizidine derivatives. Based on its properties, compound 8 was found to be the most suitable potential antitumor agent.