title: Antiproliferative and quinone reductase-inducing activities of withanolides derivatives.
abstract: Two new and five known withanolides (jaborosalactones 2, 3, 4, 5, and 24) were isolated from the leaves of Jaborosa runcinata Lam. We also obtained some derivatives from jaborosalactone 5, which resulted to be the major isolated metabolite. The natural compounds as well as derivatives were evaluated for their antiproliferative activity and the induction of quinone reductase 1 (QR1; NQ01) activity. Structure-activity relationships revealed valuable information on the pharmacophore of withanolide-type compounds. Three compounds of this series showed significantly higher antiproliferative activity than jaborosalactone 5. The effect of these compounds on the cell cycle was determined. Furthermore, the ability of major compounds to induce QR1 was evaluated. It was found that all the active test compounds are monofunctional inducers that interact with Keap1. The most promising derivatives prepared from jaborosalactone 5 include (23R)-4β,12β,21-trihydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-olide (18) and (23R)-21-acetoxy-12β-hydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen-26,23-lactame (20).
authors.affiliation: Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Casilla de Correo 495, X5000HUA Córdoba, Argentina. Electronic address: manuelagarcia@fcq.unc.edu.ar.
authors.forename: Manuela E
authors.initials: ME
authors.lastname: García
authors.affiliation: Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Casilla de Correo 495, X5000HUA Córdoba, Argentina.
authors.forename: Viviana E
authors.initials: VE
authors.lastname: Nicotra
authors.affiliation: Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, X5000HUA Córdoba, Argentina; Instituto Multidisciplinario de Biología Vegetal (IMBIV-CONICET), Casilla de Correo 495, X5000HUA Córdoba, Argentina.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Oberti
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Ríos-Luci
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
authors.forename: Leticia G
authors.initials: LG
authors.lastname: León
authors.affiliation: The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, 96720 HI, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Marler
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, 60612 IL, USA.
authors.forename: Guannan
authors.initials: G
authors.lastname: Li
authors.affiliation: The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 34 Rainbow Drive, Hilo, 96720 HI, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, 60612 IL, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Padrón
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
authors.forename: Idaira
authors.initials: I
authors.lastname: Hueso-Falcón
authors.affiliation: Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D011808:Quinone Reductases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D054358:Withanolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D054358:Withanolides; D011808:Quinone Reductases
keywords: Antiproliferative activity; Jaborosa runcinata; Keap1 protein; Quinone-reductase induction; Withanolide derivatives