title: Novel B-ring modified allocolchicinoids of the NCME series: design, synthesis, antimicrotubule activity and cytotoxicity.
abstract: Two new series of allocolchicinoids mimicking the structure of (-)-N-acetylcolchinol O-methyl ether (2, NCME) were synthesized and evaluated for their abilities to inhibit tubulin assembly. Possible antitumor properties resulting thereof were evaluated in vitro on the human MCF-7 breast cancer cell line. The first series of NCME-derivatives was brought about by extending the seven membered B-ring to novel semisynthetic variations with a nitrogen containing eight-membered B-ring similar, for example, to the artificial, potent steganacin aza-analogue 3. In the second series the seven-membered B-ring of NCME (2) was modified by annulation with a heterocyclic ring system. The racemic ketone 7a serving as key precursor involved in the syntheses of all the target NCME variants 9-13 and 15, 16 was easily transformed into the eight-membered B-ring lactams 9 and 10 via a Beckmann rearrangement of the corresponding E-oxime 8. The tetrazole annulated congener 11 was prepared via azidotrimethylsilane-mediated Schmidt rearrangement. Treatment of educt 7a with Bredereck's reagent led to the enamino ketone 14, which was easily converted into the pyrazole- or pyrimidine-annulated allocolchicinoids 15 and 16. Remarkably, all the allocolchicinoids 9-13 with an azocin-B-ring affected the tubulin/microtubule equilibrium only moderately. In contrast, the novel heterocycle annulated seven membered B-ring variants 15 and 16 proved to be highly potent tubulin-inhibitory, antimitotic agents. Interaction with tubulin occured at concentrations similar to those observed for colchicine (1) or the lead NCME (2). In all cases the antiproliferative effects correlated roughly with the inhibition of tubulin assembly.
authors.affiliation: Institut für Pharmazie I der Freien Universität Berlin, Königin-Luise-Str. 2 u. 4, D-14195, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Bergemann
authors.forename: René
authors.initials: R
authors.lastname: Brecht
authors.forename: Frank
authors.initials: F
authors.lastname: Büttner
authors.forename: Daniel
authors.initials: D
authors.lastname: Guénard
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Gunther
authors.initials: G
authors.lastname: Seitz
authors.forename: Milton T
authors.initials: MT
authors.lastname: Stubbs
authors.forename: Sylviane
authors.initials: S
authors.lastname: Thoret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D017550:Spectroscopy, Fourier Transform Infrared; D014404:Tubulin / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D014404:Tubulin; D003078:Colchicine