Synthesis of indolizidinone analogues of cytotoxic alkaloids: monocyclic precursors are also active |
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Authors: | Boto Alicia Miguélez Javier Marín Raquel Díaz Mario |
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Institution: | Instituto de Productos Naturales y Agrobiología del CSIC, La Laguna, Tenerife, Spain. alicia@ipna.csic.es |
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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. |
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