title: Total synthesis of indole-derived allocolchicine analogues exhibiting strong apoptosis-inducing activity.
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.
authors.affiliation: Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina av. 23, Nizhny Novgorod 603950, Russian Federation.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Sitnikov
authors.forename: Janna
authors.initials: J
authors.lastname: Velder
authors.forename: Liliane
authors.initials: L
authors.lastname: Abodo
authors.forename: Nicole
authors.initials: N
authors.lastname: Cuvelier
authors.forename: Jörg
authors.initials: J
authors.lastname: Neudörfl
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Günter
authors.initials: G
authors.lastname: Krause
authors.forename: Aleksey Y
authors.initials: AY
authors.lastname: Fedorov
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Schmalz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000737:chemistry* / Q000187:drug effects*; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D003078:Colchicine