- Cascade syntheses routes to the centrocountins
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Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one-pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3-formylchromones as starting materials provided evidence that this one-pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis. Rolling transformations! Various cascade synthesis routes that employ easily accessible substrates and provide efficient access to diverse tetrahydroquinolizines are disclosed (see figure). Mechanistic insights into the long cascade process that gives centrocountins are also presented. Copyright
- Eschenbrenner-Lux, Vincent,Dückert, Heiko,Khedkar, Vivek,Bruss, Hanna,Waldmann, Herbert,Kumar, Kamal
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p. 2294 - 2304
(2013/03/28)
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- SUBSTITUTED INDOLO [2,3-A] QUINOLIZINES
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The present invention relates to novel substituted indolo[2,3-a]quinolizines and stereoisomeric forms thereof and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted indolo[2,3-a]quinolizines together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted indolo[2,3-a]quinolizines have been identified as useful for the prophylaxis and treatment of cancer by the induction of strong mitotic delays, chromosomal misalignments and mitotic tri- and multipolarization leading to cell cycle stop and apoptosis. Furthermore a synthesis for preparation of the substituted indolo[2,3-a]quinolizines is disclosed in the present invention.
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Page/Page column 20
(2013/02/27)
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- Substituted indolo [2,3-a] quinolizines in the treatment of cancer
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The present invention relates to novel substituted indolo [2,3-a] quinolizines of the general formula (I) and stereoisomeric forms thereof and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted indolo [2,3-a] quinolizines together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted indolo [2,3-a] quinolizines have been identified as useful for the prophylaxis and treatment of cancer by the induction of strong mitotic delays, chromosomal misalignments and mitotic tri- and multipolarization leading to cell cycle stop and apoptosis. Furthermore a synthesis for preparation of the substituted indolo [2,3-a] quinolizines is disclosed in the present invention.
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Page/Page column 27-28
(2013/02/27)
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- Natural product-inspired cascade synthesis yields modulators of centrosome integrity
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In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.
- Dückert, Heiko,Pries, Verena,Khedkar, Vivek,Menninger, Sascha,Bruss, Hanna,Bird, Alexander W.,Maliga, Zoltan,Brockmeyer, Andreas,Janning, Petra,Hyman, Anthony,Grimme, Stefan,Schürmann, Markus,Preut, Hans,Hübel, Katja,Ziegler, Slava,Kumar, Kamal,Waldmann, Herbert
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p. 179 - 184
(2012/06/15)
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