title: Synthesis of indolizidinone analogues of cytotoxic alkaloids: monocyclic precursors are also active.
abstract: Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission-oxidation-alkylation process, which yields 2-substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure-activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives.
authors.affiliation: Instituto de Productos Naturales y Agrobiología del CSIC, La Laguna, Tenerife, Spain. alicia@ipna.csic.es
authors.forename: Alicia
authors.initials: A
authors.lastname: Boto
authors.forename: Javier
authors.initials: J
authors.lastname: Miguélez
authors.forename: Raquel
authors.initials: R
authors.lastname: Marín
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D054836:Indolizidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D054836:Indolizidines