title: Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation.
abstract: Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, BD7 1DP, UK.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Fournier-Dit-Chabert
authors.forename: Victoria
authors.initials: V
authors.lastname: Vinader
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Santos
authors.forename: Mariano
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.forename: Aurore
authors.initials: A
authors.lastname: Dreneau
authors.forename: Ramkrishna
authors.initials: R
authors.lastname: Basak
authors.forename: Laura
authors.initials: L
authors.lastname: Cosentino
authors.forename: Gemma
authors.initials: G
authors.lastname: Marston
authors.forename: Hamdy
authors.initials: H
authors.lastname: Abdel-Rahman
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Isabel
authors.initials: I
authors.lastname: Barasoain
authors.forename: Robert A
authors.initials: RA
authors.lastname: Falconer
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D003078:Colchicine