title: Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins.
abstract: We have synthesized and assayed dimethylaminophenyl, pyrrolidin-1-ylphenyl and carbazole containing phenstatins and isocombretastatins as analogues of the highly potent indoleisocombretastatins with extended or reduced ring sizes. This is an attempt to explore beyond the structural constraints of the X-ray crystal structures the zone of the colchicine site where the tropolone ring of colchicine binds to tubulin (zone 1). The isocombretastatins display up to 30 fold increased water solubility when compared with combretastatin A-4, potent inhibition of tubulin polymerization, and nanomolar cytotoxicities against several human cancer cell lines irrespective of the size of the B ring. On the other hand, substitutions ortho to the nitrogen cause an important reduction in potency. We have also shown that representative compounds inhibit autophagy. These results show that zone 1 can adapt to systems of different size as far as they stay in a common plane, but does not tolerate substituents protruding above or below it. These results can help in the understanding of the binding modes of structures with similar systems and in the design of new colchicine site ligands.
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jiménez
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain; Faculté des Sciences, Departement de Chimie, Université Abdelmalek Essâadi, Tetouan, Morocco.
authors.forename: Younes
authors.initials: Y
authors.lastname: Ellahioui
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Álvarez
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Aramburu
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Riesco
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Myriam
authors.initials: M
authors.lastname: González
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Vicente
authors.affiliation: Faculté des Sciences, Departement de Chimie, Université Abdelmalek Essâadi, Tetouan, Morocco.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Dahdouh
authors.affiliation: Faculté des Sciences, Departement de Chimie, Université Abdelmalek Essâadi, Tetouan, Morocco.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibn Mansour
authors.affiliation: Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, IBSAL and Laboratorio de Diagnóstico en Cáncer Hereditario, Laboratorio 14, Instituto de Biología Molecular y Celular Del Cáncer, Universidad de Salamanca-CSIC, E-37007 Salamanca, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Jiménez
authors.affiliation: Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, IBSAL and Laboratorio de Diagnóstico en Cáncer Hereditario, Laboratorio 14, Instituto de Biología Molecular y Celular Del Cáncer, Universidad de Salamanca-CSIC, E-37007 Salamanca, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Martín
authors.affiliation: Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, IBSAL and Laboratorio de Diagnóstico en Cáncer Hereditario, Laboratorio 14, Instituto de Biología Molecular y Celular Del Cáncer, Universidad de Salamanca-CSIC, E-37007 Salamanca, Spain.
authors.forename: Rogelio G
authors.initials: RG
authors.lastname: Sarmiento
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Medarde
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Caballero
authors.affiliation: Laboratorio de Química Orgánica y Farmacéutica, Facultad de Farmacia, CIETUS (Centro de Enfermedades Tropicales) and IBSAL (Instituto de Investigación Biomédica de Salamanca), Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain. Electronic address: pelaez@usal.es.
authors.forename: Rafael
authors.initials: R
authors.lastname: Peláez
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010316:Particle Size; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin; D009584:Nitrogen; D003078:Colchicine
keywords: Autophagy; Cytotoxicity; Isocombretastatins; Phenstatins; Tubulin polymerization inhibition; para-Nitrogen-substituted