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Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity |
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| Authors: | Nikolay Sitnikov Dr. Janna Velder Liliane Abodo Nicole Cuvelier Dr. Jörg Neudörfl Dr. Aram Prokop Dr. Günter Krause Prof. Dr. Aleksey Y. Fedorov Prof. Dr. Hans‐Günther Schmalz |
| Affiliation: | 1. Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina av. 23, Nizhny Novgorod 603950 (Russian Federation), Fax: (+7)?831‐462‐30‐85;2. Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 K?ln (Germany), Fax: (+49)?221‐470‐3064;3. Department of Pediatric Hematology/Oncology, Children's Hospital K?ln, Amsterdamer Strasse 59, 50735 K?ln (Germany);4. Department I of Internal Medicine, Center for Integrated Oncology K?ln Bonn, University of Cologne, Kerpener Strasse 62, 50937 K?ln (Germany) |
| Abstract: | A series of novel pyrrolo‐allocolchicine derivatives (containing a 1‐methyl‐1H‐indol‐5‐yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki–Miyaura cross‐coupling of a 1‐methylindole‐5‐boronate with an ortho‐iodo‐dihydrocinnamic acid derivative and subsequent intramolecular Friedel–Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu‐type reaction by using zinc azide followed by LiAlH4 reduction. Structural assignments were supported by X‐ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub‐nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines. |
| Keywords: | allocolchicinoids atropisomerism cross‐coupling heterocycles antitumor agents |