Semisynthesis and Evaluation of Anti-Inflammatory Activity of the Cassane-Type Diterpenoid Taepeenin F and of Some Synthetic Intermediates

A new strategy for the semisynthesis of the aromatic cassane-type diterpene taepeenin F (6) is reported. The introduction of the methyl group at C-14, characteristic of the target compound, was achieved via dienone 13, easily prepared from abietic acid (10), the major compound in renewable rosin. Biological assays of selected compounds are reported. The antiproliferative activity against HT29, B16-F10, and HepG2 tumor cell lines has been investigated. Salicylaldehyde 21 was the most active compound (IC50 = 7.72 μM). Products 16 and 21 displayed apoptotic effects in B16-F10 cells, with total apoptosis rates of 46 and 38.4%, respectively. This apoptotic process involves a significant arrest of the B16-F10 cell cycle, blocking the G0/G1 phase. Dienone 16 did not cause any loss of the mitochondrial membrane potential (MMP), while salicylaldehyde 21 caused a partial loss of the MMP. The anti-inflammatory activity of the selected compounds was investigated with the LPS-stimulated RAW 264.7 macrophages. All compounds showed potent NO inhibition, with percentages between 80 and 99% at subcytotoxic concentrations. Dienone 16 inhibited LPS-induced differentiation of RAW 264.7 cells, by increasing the proportion of cells in the S phase. In addition, salicylaldehyde 21 had effects on the cell cycle, recovering the cells from the G0/G1 full arrest produced in response to LPS action.Junta de Andalucia B-FQM-278-UGR20 B-FQM-650-UGR20 FQM-348 BIO-157Universidad de Granada/CBU

Synthesis and Biological Evaluation of Cassane Diterpene (5 alpha)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 +/- 0.04 mu g/mL and 5.71 +/- 0.14 mu g/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 mu g/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.Junta de Andalucia BFQM-278-UGR20 B-FQM-650-UGR2

Synthesis of Tricyclic Pterolobirin H Analogue: Evaluation of Anticancer and Anti-Inflammatory Activities and Molecular Docking Investigations

This research was funded by grants from the Regional Government of Andalusia (Projects B-FQM-278-UGR20, B-FQM-650-UGR-20), and assistance was provided to the group FQM-348.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28176208/s1Pterolobirin H (3), a cassane diterpene isolated from the roots of Pterolobium macropterum, exhibits important anti-inflammatory and anticancer properties. However, its relatively complex tetracyclic structure makes it difficult to obtain by chemical synthesis, thus limiting the studies of its biological activities. Therefore, we present here a short route to obtain a rational simplification of pterolobirin H (3) and some intermediates. The anti-inflammatory activity of these compounds was assayed in LPS-stimulated RAW 264.7 macrophages. All compounds showed potent inhibition of NO production, with percentages between 54 to 100% at sub-cytotoxic concentrations. The highest anti-inflammatory effect was shown for compounds 15 and 16. The simplified analog 16 revealed potential NO inhibition properties, being 2.34 higher than that of natural cassane pterolobirin H (3). On the other hand, hydroxyphenol 15 was also demonstrated to be the strongest NO inhibitor in RAW 264.7 macrophages (IC50 NO = 0.62 ± 0.21 μg/mL), with an IC50NO value 28.3 times lower than that of pterolobirin H (3). Moreover, the anticancer potential of these compounds was evaluated in three cancer cell lines: HT29 colon cancer cells, Hep-G2 hepatoma cells, and B16-F10 murine melanoma cells. Intermediate 15 was the most active against all the selected tumor cell lines. Compound 15 revealed the highest cytotoxic effect with the lowest IC50 value (IC50 = 2.45 ± 0.29 μg/mL in HT29 cells) and displayed an important apoptotic effect through an extrinsic pathway, as evidenced in the flow cytometry analysis. Furthermore, the Hoechst staining assay showed that analog 15 triggered morphological changes, including nuclear fragmentation and chromatin condensation, in treated HT29 cells. Finally, the in silico studies demonstrated that cassane analogs exhibit promising binding affinities and docking performance with iNOS and caspase 8, which confirms the obtained experimental results.Regional Government of Andalusia B-FQM-278-UGR20, B-FQM-650-UGR-20, FQM-34

Evaluation of Anticancer and Anti-Inflammatory Activities of Some Synthetic Rearranged Abietanes

This research was funded by grants from the Regional Government of Andalusia (Projects B-FQM-278-UGR20, and B-FQM-650-UGR-20), and assistance was provided to the group FQM-348.Supplementary Materials: The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijms241713583/s1Synthesis of the rearranged abietane diterpenes pygmaeocins C and D, viridoquinone, saprorthoquinone, and 1-deoxyviroxocine has been successfully achieved. The anticancer and anti-inflammatory activities of selected orthoquinonic compounds 5, 7, 13, and 19, as well as pygmaeocin C (17), were evaluated for the first time. The antitumor properties were assessed using three cancer cell lines: HT29 colon cancer cells, Hep G2 hepatocellular carcinoma cells, and B16-F10 murine melanoma cells. Compounds 5 and 13 showed the highest cytotoxicity in HT29 cells (IC50 = 6.69 ± 1.2 µg/mL and IC50 = 2.7 ± 0.8 µg/mL, respectively). Cytometric studies showed that this growth inhibition involved phase S cell cycle arrest and apoptosis induction, possibly through the activation of the intrinsic apoptotic pathway. Morphological apoptotic changes, including nuclear fragmentation and chromatin condensation, were also observed. Furthermore, the anti-inflammatory activity of these compounds was evaluated on the basis of their ability to inhibit nitric oxide production on the lipopolysaccharide activated RAW 264.7 macrophage cell line. Although all compounds showed high anti-inflammatory activity, with percentages between 40 and 100%, the highest anti-inflammatory potential was obtained by pygmaeocin B (5) (IC50NO = 33.0 ± 0.8 ng/mL). Our results suggest that due to their dual roles, this type of compound could represent a new strategy, contributing to the development of novel anticancer agents.Regional Government of Andalusia B-FQM-278-UGR20, B-FQM-650-UGR-20, FQM-34

3-hetero-1,5-dialdehidos : síntesis, estructura y propiedades dl iminodiacetaldehido y derivados n-sustituidos

Univ. Granada, Facultad de Ciencias. Leída el 29-03-198

Method for preparing systhesis intermediates that can be used in the preparation of taiwaniaquinoids

Número de publicación: ES2341835 B1. Número de solicitud: 200900048.La invención se refiere a un método para la obtención de taiwaniaquinoids tienen la fórmula general (13), que se puede utilizar como intermedios de síntesis en la producción de otros taiwaniaquinoids y derivados. El método comprende la condensación entre alfa-ciclocitral o beta-ciclocitral y un derivado halogenado que tiene la fórmula (11) con el fin de obtener un compuesto que tiene la fórmula (12), el cual es posteriormente ciclado y deshidratado por medio de un tratamiento ácido para producir la estructura tricíclica [6-5-6] de los taiwaniaquinoids.The invention relates to a method for obtaining taiwaniaquinoids having general formula (13), which can be used as synthesis intermediates in the production of other taiwaniaquinoids and derivatives. The method comprises the condensation between alpha-cyclocitral or beta-cyclocitral and a halogenated derivative having formula (11) in order to obtain a compound having formula (12), which is subsequently cyclized and dehydrated by means of acid treatment to produce the tricyclic structure [6-5-6] of the taiwaniaquinoids.Universidad de Granad

Procedimiento para la preparación de merosesquiterpenos y compuestos relacionados a partir de diterpenos labdánicos

Número de publicación: ES2327196 B2. Número de solicitud: 200800837.Procedimiento para la preparación de merosesquiterpenos a partir de diterpenos labdánicos. La presente invención describe un procedimiento para la obtención de merosesquiterpenos, más concretamente drimenilbencenos y drimenilnaftoquinonas, mediante una reacción Diles Alder entre un diterpeno labdánico y un dienófilo. A continuación una deshidrogenación conduce a los derivados aromatizados.Universidad de Granad

Procedimiento para la preparación de hidroxitirosol y 3-(3,4-dihidroxifenil)propanol a partir de metilendioxibencenos

Número de publicación: ES2332635 B2. Número de solicitud: 200801967.Procedimiento para la preparación de hidroxitirosol Y 3-(3,4-dihidroxifenil)propanol a partir de metilendioxibencenos. La presente invención describe un procedimiento para obtención de un compuesto de fórmula general (II) que comprende tratar un compuesto metilendioxibenceno de fórmula general (I) con una sal alcalina o alcalina térrea de un glicol, en el seno de un disolvente polar aprótico y donde el sustituyente R representa un grupo seleccionado de entre un grupo alquilo, alquenilo y alquinilo, C1-C4 lineal o ramificado, opcionalmente sustituido en al menos uno de los C, con al menos un grupo seleccionado de entre -OH, -CO-, -NH{sub,2}, -COOH y -COOR', y donde R' es un grupo alquilo C1-C4 lineal o ramificado. Los compuestos de fórmula (I) se obtienen ventajosamente a partir de safrol o piperonal.Universidad de Granad

Procedimiento para la preparación de derivados de 1,1,2-trialquil-1H-indeno a partir de derivados de 2-(1,1,2-trialquil-3-oxopropil)benzaldehído

Número de publicación: ES2547027 B1. Número de solicitud: 201531158.Procedimiento para la preparación de derivados de 2-alquil-1H-indeno y 2, 3, 4, 4ª-tetrahidro-1H-fluoreno a partir de derivados de 2–(2–alquil–3–oxopropil) benzaldehído y 2–(2–formilciclohexil) benzaldehído, respectivamente. La presente invención describe un procedimiento para la preparación de derivados de 2–alquil–1H–indeno y tratamiento ácido de derivados de 2–(2-alquil-3-oxopropil) benzaldehído y 2–(2–formilciclohexil) benzaldehído, respectivamente.Universidad de Granad

Procedimiento para la preparación de merosesquiterpenos mediante cicloadición de Diels Alder de dienos derivados de diterpenos

Número de publicación: ES2563602 B1. Número de solicitud: 201400746.Universidad de GranadaUniversité Abdelmalek Essaâd