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Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity
Author(s) -
Sitnikov Nikolay,
Velder Janna,
Abodo Liliane,
Cuvelier Nicole,
Neudörfl Jörg,
Prokop Aram,
Krause Günter,
Fedorov Aleksey Y.,
Schmalz HansGünther
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200083
Subject(s) - moiety , chemistry , ketone , stereochemistry , azide , ring (chemistry) , indole test , apoptosis , intramolecular force , medicinal chemistry , organic chemistry , biochemistry
A series of novel pyrrolo‐allocolchicine derivatives (containing a 1‐methyl‐1 H ‐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.