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

Síntesis de productos naturales y derivados con actividad antiparasitaria y antitumoral a partir de ácido abiético

La presente tesis doctoral se estructura en cuatro capítulos. En el primero se aborda la síntesis de diferentes fenoles funcionalizados en C-18 como son hanagokenol A, fortuninos E; G; y H, metabolitos aislados de recursos naturales de Asia. Para ello primero se transforma el material de partida ácido (-)-abiético en el 18-hidroxiferruginol. En este capítulo también se presenta una estrategia eficaz de inversión de la funcionalización sobre C-4 vía alqueno exocíclico. Esta nueva estrategia nos permitió abordar la síntesis de diferentes metabolitos funcionalizados en C-19 como son el 19-hidroxiferruginol y sujikurogina A. En el segundo capítulo se desarrolla una nueva metodología para la transposición del metilo angular sobre C-10 a C-5 de derivados 6, 8, 11, 13-abietatetraenos, así como de derivados de tipo quinona. Estos resultados nos permitió realizar una aproximación sintética hacia pydmeacins B, C y salviskinona A, productos naturales con este inusual esqueleto carbocíclico. Además se realiza un estudio de oxidación de En el tercer capítulo se aborda una metodología que permite acceder de manera rápida y económica a una familia de diterpenos y norditerpenos con esqueleto de 4a-metilhexahidro o 4a-metiltetrahidro fluoreno. Estos metabolitos se han aislado de diferentes coníferas del sudeste asiático. También se realiza la síntesis de derivados de estos compuestos con diferente grado de oxidación. También se desarrolla una nueva metodología de ciclación de seco-abietanos dialdehídos mediada por ácido, no descrita hasta la fecha en bibliografía, que permite una rápida obtención de la estructura de 4a-tetrahidrofluoreno. Con ello se realiza la síntesis de taxodal y cupresol (a los que denominamos seco-taiwaniaquinoides), metabolitos relacionados con estos taiwaniaquinoides, ya que se pueden considerar productos de la ruptura oxidativa del doble enlace presente en el anillo B. En el último capítulo de esta tesis doctoral se presentan los resultados de los ensayos de actividad antiparasitaria (contra la enfermedad de Chagas) y antitumorales de algunos de los metabolitos sintetizados en los anteriores capítulos.Tesis Univ. Granada. Programa Oficial de Doctorado en: QuímicaFinanciación concedida por el Ministerio de Ciencia e Innovación (Proyecto CTQ2009-09932) y la Junta de Andalucía (Proyecto P11-CTS-7651 y ayuda al grupo de investigación FQM-348 “Productos Naturales y Síntesis Orgánica Aplicada”

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

PCR-free and chemistry-based technology for miR-21 rapid detection directly from tumour cells

miRNAs play pivotal roles in various biological contexts, particularly in disease. Notably, miRNA-21 is implicated in severe pathological conditions, necessitating accurate quantification for medical diagnostics. Existing miRNA quantification techniques often fall short. Here, we introduce a novel, dynamic chemistry-based, PCR-free method for rapid and cost-effective miRNA-21 identification and quantification directly from tumor cells, employing FACS and fluorescent microplate assays. This approach, utilizing bead-based reagents, enables precise quantification of miR-21 molecules in MDA-MB-468 and H1975 tumor cells.This research was supported by the Regional Government, Spain(BIO-1778) and the Ministry of Economy and Competitiveness, Spain(BIO2016-80519-R – FJLD is supported by Torres Quevedo fellowship,SpainPTQ-16-08597).ADGandARRaresupportedbySpanishMinistryof Education, Spain (PhD scholarships FPU14/02181 and FPU15/06418, respectively). AMR thanks DestiNA Genomics, Spain and theUniversity of Granada, Spain for a PhD scholarship (P26 KnowledgeTransferProgramme)DMPacknowledgestheUniversityofGranadaforhis predoctoral research contract. SD's work was supported by in-tramural funding from the University of Trento, Italy. DestiNA's staffand SD thank the miRNADisEASY Consortium (EU, European UnionH2020-MSCA-RISE 2015 (Grant no. 690866)). We would also like tothank all the healthy volunteers who participated in this study

Development of a nanotechnology-based approach for capturing and detecting nucleic acids by using flow cytometry

Nucleic acid-based molecular diagnosis has gained special importance for the detection and early diagnosis of genetic diseases as well as for the control of infectious disease outbreaks. The development of systems that allow for the detection and analysis of nucleic acids in a low-cost and easy-to-use way is of great importance. In this context, we present a combination of a nanotechnology-based approach with the already validated dynamic chemical labeling (DCL) technology, capable of reading nucleic acids with single-base resolution. This system allows for the detection of biotinylated molecular products followed by simple detection using a standard flow cytometer, a widely used platform in clinical and molecular laboratories, and therefore, is easy to implement. This proof-of-concept assay has been developed to detect mutations in KRAS codon 12, as these mutations are highly important in cancer development and cancer treatments.This research was supported by the Spanish Ministry of Economy and Competitiveness (grant number BIO2016-80519). The authors are members of the NANOCARE network (RED2018-102469-T) funded by the STATE INVESTIGATION AGENCY. ARR thanks the Spanish Ministry of Education for PhD funding (scholarship FPU15/06418). FJ Lopez Delgado thanks the Spanish Ministry of Economy and Competitiveness for the Torres Quevedo fellowship (PTQ-16- 08597). These studies were approved and supported by DestiNA Genomics Ltd. Schemes in Figs. 1 and 4–6 have been partially created using BioRender.com

Development of a nanotechnology-based approach for capturing and detecting nucleic acids by using flow cytometry.

Nucleic acid-based molecular diagnosis has gained special importance for the detection and early diagnosis of genetic diseases as well as for the control of infectious disease outbreaks. The development of systems that allow for the detection and analysis of nucleic acids in a low-cost and easy-to-use way is of great importance. In this context, we present a combination of a nanotechnology-based approach with the already validated dynamic chemical labeling (DCL) technology, capable of reading nucleic acids with single-base resolution. This system allows for the detection of biotinylated molecular products followed by simple detection using a standard flow cytometer, a widely used platform in clinical and molecular laboratories, and therefore, is easy to implement. This proof-of-concept assay has been developed to detect mutations in KRAS codon 12, as these mutations are highly important in cancer development and cancer treatments

Dataset from article 'A New Horizon in Multiplexed micro-RNA Biomarker Detection: Bridging Lifetime Filtering Imaging and Dynamic Chemistry Labeling'

MicroRNAs (miRs) have emerged as promising biomarkers for early disease diagnosis and personalised treatment monitoring. However, but their clinical utility has been hampered by technical limitations. Dynamic chemical labelling (DCL) based on capturing abasic PNA probes and reactive nucleobases, so-called SMART bases, is a PCR-free approach that has proven very useful for the direct interrogation of circulating miRs. In this work, we expand the palette of available tools for DCL miR detection methods with a newly synthesised SMART nucleobase, SMART-C-Eu. This nucleobase contains a stable lanthanide cryptate. Using this SMART-C-Eu base and time-gated (TG) luminescence imaging, we successfully detect and quantify miR-122-5p in human serum samples. miR-122-5p is a well-known biomarker for drug-induced liver injury. A bead-counting analysis approach improved statistical robustness and allowed the detection of miR-122-5p concentrations in the nanomolar range. Furthermore, we extend this approach to multiplexed detection of three different miRs (miR-371a-3p, miR-451a-5p, and miR-122-5p) using spectral and temporal filtering. Consistent results were obtained using machine learning algorithms for automatic bead classification. Although this technique requires further sensitivity improvements to detect miRs at lower concentrations, it represents a significant advancement in miR analysis. It offers multiplexing capabilities and the potential for automation, paving the way for more accurate and robust clinical applications in the future.European Union through the H2020 diaRNAgnosis project, under grant agreement No. 101007934Agencia Estatal de Investigación (Spain) through grant PID2020-114256RB-I00 AEI/10.13039/501100011033Agencia Estatal de Investigación (Spain) through grant CTQ2017-85658-R AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”

Actividad antitumoral de taiwaniaquinoides y compuestos relacionados

Número de publicación: ES2430604 B1. Número de solicitud: 201200438.La invención define el uso de un compuesto de fórmula general para la fabricación de un medicamento para el tratamiento y/o profilaxis de un cáncer sólido seleccionado entre cáncer de mama, cáncer colorrectal, cáncer de pulmón, cáncer de páncreas, cáncer hepático y neuroblastoma; y en el tratamiento y/o profilaxis de síndromes mieloproliferativos agudos y crónicos.Universidad de GranadaFundación Pública Andaluza para la Investigación Biosanitaria de Andalucía Oriental (FIBAO