title: Novel cyanocombretastatins as potent tubulin polymerisation inhibitors.
abstract: A series of novel cyanocombretastatins bearing a 3,4,5-trimethoxyphenyl moiety combined with a variety of substituted phenyl rings, were synthesised and their antitumour activity was evaluated. The Z-cyanocombretastatins were synthesised in a one-step protocol in high purity and yield. Fluoro, bromo, iodo, and derivatives with boronic acid and an ethyne function at meta position of the B ring were synthesised. In vitro MTT bioassays against human chronic myelogenous leukaemia (K562) and transfected breast adenocarcinoma (MDA NQO1) cell lines, revealed promising IC(50) inhibitory values in nanomolar range (<50 nM). Introduction of a nitrile function on the olefinic bond not only increased the cytotoxicity of the less active Z-isomers but rendered the analogues as moderate to potent inhibitors of tubulin polymerisation comparable to that of CA-4 (IC(50)=2.2 μM).
authors.affiliation: KidsCan Research Laboratories, Centre for Biochemistry, Drug Design and Cancer Research, School of Environment and Life Sciences, University of Salford, M5 4WT, UK.
authors.forename: Pouria H
authors.initials: PH
authors.lastname: Jalily
authors.forename: John A
authors.initials: JA
authors.lastname: Hadfield
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hirst
authors.forename: Steven B
authors.initials: SB
authors.lastname: Rossington
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D009570:Nitriles; D050257:Tubulin Modulators; C040105:combretastatin