title: Synthesis, Biological Profiling and Determination of the Tubulin-Bound Conformation of 12-Aza-Epothilones (Azathilones).
abstract: 12-Aza-epothilones (azathilones) incorporating quinoline side chains and bearing different N12-substituents have been synthesized via highly efficient RCM-based macrocyclizations. Quinoline-based azathilones with the side chain N-atom in the meta-position to the C15 atom in the macrocycle are highly potent inhibitors of cancer cell growth in vitro. In contrast, shifting the quinoline nitrogen to the position para to C15 leads to a ca. 1000-fold loss in potency. Likewise, the desaturation of the C9-C10 bond in the macrocycle to an E double bond produces a substantial reduction in antiproliferative activity. This is in stark contrast to the effect exerted by the same modification in the natural epothilone macrocycle. The conformation of a representative azathilone bound to α/β-tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on β-tubulin was deduced through a combination of STD measurements and CORCEMA-ST calculations. The tubulin-bound, bioactive conformation of azathilones was found to be overall similar to that of epothilones A and B.
authors.affiliation: Department of Chemistry and Applied Biosciences, Insitute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland. a.jantsch@hotmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jantsch
authors.affiliation: Department of Organic Chemistry I, Fac. C. C. Químicas, Universidad Complutense de Madrid, ES-28040 Madrid, Spain. linietog@gmail.com.|Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. linietog@gmail.com.
authors.forename: Lidia
authors.initials: L
authors.lastname: Nieto
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland. juerg.gertsch@ibmm.unibe.ch.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. javierr@cib.csic.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez-Salarichs
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. ruth.m.r@cib.csic.es.
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.affiliation: CIC bioGUNE, 48170 Derio, Spain. jjbarbero@cicbiogune.es.|Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain. jjbarbero@cicbiogune.es.|Department of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country, 48940 Leioa, Bizkaia, Spain. jjbarbero@cicbiogune.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain. fer@cib.csic.es.
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.affiliation: Department of Organic Chemistry I, Fac. C. C. Químicas, Universidad Complutense de Madrid, ES-28040 Madrid, Spain. angelescm@cib.csic.es.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Canales
authors.affiliation: Department of Chemistry and Applied Biosciences, Insitute of Pharmaceutical Sciences, ETH Zürich, CH-8093 Zürich, Switzerland. karl-heinz.altmann@pharma.ethz.ch.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin
keywords: SAR; STD; anticancer; azathilones; conformation; drug discovery; epothilones; natural product; synthesis; tubulin