Simplification of antitumoral phenanthroindolizidine alkaloids: Short synthesis of cytotoxic indolizidinone and pyrrolidine analogs

Hydroxylated seco-analogs of cytotoxic phenanthroindolizidine alkaloids were prepared in good yields from inexpensive 4-hydroxyproline derivatives, in just two steps. Thus, a sequential oxidative radical scissioneoxidation was used for the direct conversion of the proline derivative into a 2-(2-aryl-oxoethyl) pyrrolidine with a variety of aryl and heteroaryl groups. The 4R-stereogenic center allowed ready isomer separation, and stereocontrol in the introduction of new chains (interestingly, the 2,4-cis isomers predominated). In the second step, a cyclization reaction afforded alkaloid analogs with an indolizidinone core; a partial isomerization took place but the isomers were readily purified. Then the cytotoxic activity of the bicyclic indolizidinones and the simpler pyrrolidine derivatives was compared against tumorogenic human neuronal SHSY-5Y and breast cancer MCF7 cells. All the biphenyl derivatives displayed a potent activity (one derivative caused >80% cell death in both tumor lines at micromolar dosis), being comparable in the pyrrolidine and indolizidinone series.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, currently Economia y Competitividad, Spain), and Proyectos Intramurales 2004-8-0E211 and 2004-80E642 (CSIC, Spanish Research Council, Spain). We also acknowledge financial support from FEDER (European Funds for Regional Development). J. M. thanks CSIC for a JAE predoctoral fellowship.N