Identification of Anti-Proliferative Compounds from Genista monspessulana Seeds through Covariate-Based Integration of Chemical Fingerprints and Bioactivity Datasets

Abstract

Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) is a Mediterranean plant introduced to South America and other regions for ornamental purposes. However, it is considered an invasive shrub due to its reproductive vigor in many areas. Unlike other Genista plants, G. monspessulana has few studies disclosing its biologically active components, particularly cytotoxic agents against cancer cells. Thus, as part of our research on anti-proliferative bioactives, a set of ethanolic seed extracts from ten accessions of G. monspessulana, collected in the Bogotá plateau, were evaluated against four cell lines: PC-3 (prostate adenocarcinoma), SiHa (cervical carcinoma), A549 (lung carcinoma), and L929 (normal mouse fibroblasts). Extracts were also analyzed through liquid chromatography coupled with mass spectrometry (LC/MS) to record chemical fingerprints and determine the composition and metabolite variability between accessions. Using multiple covariate statistics, chemical and bioactivity datasets were integrated to recognize patterns and identify bioactive compounds among studied extracts. G. monspessulana seed-derived extracts exhibited dose-dependent antiproliferative activity on PC-3 and SiHa cell lines (>500 µg/mL < IC50 < 26.3 µg/mL). Seven compounds (1–7) were inferred as the compounds most likely responsible for the observed anti-proliferative activity and subsequently isolated and identified by spectroscopic techniques. A tricyclic quinolizidine (1) and a pyranoisoflavone (2) were found to be the most active compounds, exhibiting selectivity against PC-3 cell lines (IC50 < 18.6 µM). These compounds were used as precursors to obtain a quinolizidine-pyranoisoflavone adduct via Betti reaction, improving the activity against PC-3 and comparable to curcumin as the positive control. Results indicated that this composition–activity associative approach is advantageous to finding those bioactive principles efficiently within active extracts. This correlative association can be employed in further studies focused on the targeted isolation of anti-proliferative compounds from Genista plants and accessions. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Genista monspessulana (L.) L.A.S. Johnson (Fabaceae) es una planta mediterránea introducida en América del Sur y otras regiones con fines ornamentales. Sin embargo, se considera un arbusto invasor debido a su vigor reproductivo en muchas zonas. A diferencia de otras plantas Genista, G. monspessulana tiene pocos estudios que revelen sus componentes biológicamente activos, particularmente agentes citotóxicos contra las células cancerosas. Así, como parte de nuestra investigación sobre bioactivos antiproliferativos, se evaluó un conjunto de extractos etanólicos de semillas de diez accesiones de G. monspessulana, recolectadas en el altiplano de Bogotá, frente a cuatro líneas celulares: PC-3 (adenocarcinoma de próstata), SiHa ( carcinoma cervical), A549 (carcinoma de pulmón) y L929 (fibroblastos de ratón normales). Los extractos también se analizaron mediante cromatografía líquida junto con espectrometría de masas (LC/MS) para registrar huellas químicas y determinar la composición y la variabilidad de los metabolitos entre las muestras. Utilizando múltiples estadísticas de covariables, se integraron conjuntos de datos químicos y de bioactividad para reconocer patrones e identificar compuestos bioactivos entre los extractos estudiados. Los extractos derivados de semillas de G. monspessulana exhibieron actividad antiproliferativa dependiente de la dosis en líneas celulares PC-3 y SiHa (> 500 µg/mL < IC50 < 26,3 µg/mL). Se infirieron siete compuestos (1–7) como los compuestos más probablemente responsables de la actividad antiproliferativa observada y posteriormente se aislaron e identificaron mediante técnicas espectroscópicas. Se encontró que una quinolizidina tricíclica (1) y una piranoisoflavona (2) eran los compuestos más activos y mostraban selectividad contra las líneas celulares PC-3 (IC50 < 18,6 µM). Estos compuestos se utilizaron como precursores para obtener un aducto de quinolizidina-piranoisoflavona mediante la reacción de Betti, mejorando la actividad contra PC-3 y comparable a la curcumina como control positivo.