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

AuthorsBoto, Alicia ; Miguélez, Javier ; Marín, Raquel; Díaz, Mario
Indolizidine alkaloids
Alkaloid analogues
Synthetic methodology
Sequential processes
Issue Date15-May-2012
CitationBioorganic and Medicinal Chemistry Letters 22(10): 3402-3407 (2012)
AbstractReadily 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.
Publisher version (URL)http://dx.doi.org/10.1016/j.bmcl.2012.03.109
Identifiersdoi: 10.1016/j.bmcl.2012.03.109
issn: 0960-894X
e-issn: 1464-3405
Appears in Collections:(IPNA) Artículos
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