Total synthesis of indole-derived allocolchicine analogues exhibiting strong apoptosis-inducing activity |
| |
Authors: | Nikolay Sitnikov Janna Velder Liliane Abodo Nicole Cuvelier Jörg Neudörfl Aram Prokop Günter Krause Aleksey Y Fedorov Hans-Günther Schmalz |
| |
Institution: | Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina av. 23, Nizhny Novgorod 603950 (Russian Federation), Fax: (+7)?831-462-30-85. |
| |
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 LiAlH(4) 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: | |
本文献已被 PubMed 等数据库收录! |
|