کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1392750 1501150 2013 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Simplification of antitumoral phenanthroindolizidine alkaloids: Short synthesis of cytotoxic indolizidinone and pyrrolidine analogs
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Simplification of antitumoral phenanthroindolizidine alkaloids: Short synthesis of cytotoxic indolizidinone and pyrrolidine analogs
چکیده انگلیسی


• Hydroxylated analogs of antitumoral phenanthroindolizidine alkaloids were prepared.
• A short, high-yield and stereoselective synthesis was developed.
• Several indolizidinones displayed potent cytotoxicity against MCF7 and SHSY5Y cells.
• More flexible pyrrolidine analogs were less cytotoxic except the 2-(p-biphenyls).
• SAR studies for a variety of aryl- and heteroaryl-substituted analogs are described.

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 scission–oxidation 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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 66, August 2013, Pages 540–554
نویسندگان
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