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.
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | artículo biblioteca |
| Language: | English |
| Published: |
Elsevier
2013-08
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| Subjects: | Cytotoxicity, Indolizidine, Alkaloids, Synthetic methodology, Sequential process, |
| Online Access: | http://hdl.handle.net/10261/178764 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100003339 http://dx.doi.org/10.13039/501100000780 |
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| Summary: | 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. |
|---|