Synthesis of indolizidinone analogues of cytotoxic alkaloids: Monocyclic precursors are also active

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.This work was supported by the Research Projects CTQ2009-07109 (AB) and SAF2010-22114-C02-01 (MD)/02 (RM) (Plan Nacional de I+D, Ministerio de Ciencia e Innovación, MICINN, Spain), and Proyectos Intramurales 2004-8-0E211 and 2004-80E642 (CSIC, Spanish Research Council, Spain). We also acknowledge financial support from FEDER funds. J. M. thanks CSIC for a JAE predoctoral fellowship