Antiproliferative and quinone reductase-inducing activities of withanolides derivatives
| Autor: | Leticia G. Leon, Manuela E. García, Carla Ríos-Luci, José M. Padrón, Idaira Hueso-Falcón, Ana Estévez-Braun, Viviana E. Nicotra, Laura Marler, Guannan Li, Juan C. Oberti, Richard B. van Breemen, John M. Pezzuto |
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| Rok vydání: | 2013 |
| Předmět: |
KEAP1 PROTEIN
Stereochemistry Metabolite Molecular Conformation Antineoplastic Agents Reductase QUINONE-REDUCTASE INDUCTION chemistry.chemical_compound Mice Structure-Activity Relationship JABOROSA RUNCINATA Drug Discovery Tumor Cells Cultured Animals Humans Inducer Quinone Reductases Jaborosa runcinata Withanolides Cell Proliferation Pharmacology Dose-Response Relationship Drug ANTIPROLIFERATIVE ACTIVITY Chemistry WITHANOLIDE DERIVATIVES Organic Chemistry Ciencias Químicas General Medicine Cell cycle KEAP1 Quinone Química Orgánica Biochemistry Pharmacophore Drug Screening Assays Antitumor CIENCIAS NATURALES Y EXACTAS HeLa Cells |
| Zdroj: | European journal of medicinal chemistry. 82 |
| ISSN: | 1768-3254 |
| Popis: | 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. Structureeactivity 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)-4b,12b,21-trihydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen- 26,23-olide (18) and (23R)-21-acetoxy-12b-hydroxy-1,22-dioxo-12,23-cycloergostan-2,5,17,24-tetraen- 26,23-lactame (20). Fil: García, Manuela Emila. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; Argentina Fil: Nicotra, Viviana Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; Argentina Fil: Oberti, Juan Carlos María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); Argentina. Universidad Nacional de Cordoba. Facultad de Ciencias Quimicas; Argentina Fil: Ríos Luci, Carla. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "antonio Gonzalez"; España Fil: Leon, Leticia G.. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "antonio Gonzalez"; España Fil: Marler, Laura. University of Hawaii at Hilo. The Daniel K. Inouye College of Pharmacy; Estados Unidos Fil: Li, Guannan. University of Illinois at Chicago. College of Pharmacy. Department of Medicinal Chemistry and Pharmacognosy; Estados Unidos Fil: Pezzuto, John. College Of Pharmacy, University Of Hawaii At Hilo; Fil: Van Breemen, Richard B.. University of Illinois at Chicago. College of Pharmacy. Department of Medicinal Chemistry and Pharmacognosy; Estados Unidos Fil: Padron, Jose. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "antonio Gonzalez"; España Fil: Hueso Falcon, Idaira. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "antonio Gonzalez"; España Fil: Estevez Braun, Ana. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-orgánica "antonio Gonzalez"; España |
| Databáze: | OpenAIRE |
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