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Preparation of Antiproliferative Terpene-Alkaloid Hybrids by Free Radical-Mediated Modification of ent-Kauranic Derivatives |
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| Authors: | Elena Pruteanu Vladilena Gîrbu Nicon Ungur Leentje Persoons Dirk Daelemans Philippe Renaud Veaceslav Kulci ki |
| Institution: | 1.Institute of Chemistry (MECC), Str. Academiei, 3, MD-2028 Chișinău, Moldova; (E.P.); (V.G.); (N.U.);2.Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland;3.KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium; (L.P.); (D.D.) |
| Abstract: | A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C–C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates. |
| Keywords: | diterpene ent-kaurane alkaloids radical chemistry ATRA lactam lactone spiro compound azide pyrrolidine cytotoxicity |