An Ugi–Zhu three-component reaction (UZ-3CR) coupled in a one-pot manner to a cascade process (N-acylation/aza Diels–Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of pyrrolo[3,4-b]pyridin-5-ones in 20% to 92% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against breast cancer cell lines MDA-MB-231 and MCF-7, finding that compound 1f, at a concentration of 6.25 μM, exhibited a potential cytotoxic effect. Then, to understand the interactions between synthesized compounds and the main proteins related to the cancer cell lines, docking studies were performed on the serine/threonine kinase 1 (AKT₁) and Orexetine type 2 receptor (Ox₂R), finding moderate to strong binding energies, which matched accurately with the in vitro results. Additionally, molecular dynamics were performed between proteins related to the studied cell lines and the three best ligands.

Breast cancer is the most common and the leading cause of cancer death in women worldwide; treating invasive breast carcinomas is challenging due to the side effects of chemotherapeutics. Compounds isolated from natural sources have been proposed as potential molecules for cancer therapy; for instance, the homoisoflavonoid brazilin has shown pharmacological properties, including anti-tumoral and anti-inflammatory activities. In this study, we isolated brazilin from the heartwood of Haematoxylum brasiletto; then, we performed a semi-synthesis by adding three methyl or acetyl groups to the core structure of brazilin. We confirmed the identity of brazilin and its derivatives by spectroscopic data (¹H NMR and ¹³C NMR) and measured their purity by optical rotation. Then, we analyzed the effects of brazilin and its derivatives in three mammary gland-derived cell lines: the TNBC MDA-MB-231, the ERα(+) MCF7, and the non-tumorigenic MCF10A. We evaluated the cell viability by MTT assays, cell migration by wound-healing assays, and focal adhesion kinase (FAK) activation by Western blot. Regarding biological assays, the MTT assay showed that these compounds showed cytotoxic effects on the MCF7 and MDA-MB-231 breast cancer cells at 20 µM but was not toxic in non-tumorigenic MCF10A mammary epithelial cells. Specifically, the greatest effects found from treatment with the compounds were in the MDA-MB-231 cell line, where the IC50 of brazilin was 49.92 μM, and for MCF7, the brazilin-(OAc)₃ was 49.97 μM. These effects were dose- and time-dependent, as well as being associated with a decrease in the levels of cell migration and FAK activation.

El plomo es un metal pesado que se encuentra de forma natural en la corteza terrestre; sin embargo, por las actividades antropogénicas es liberado al ambiente ocasionando la contaminación del aire, suelo y agua. Una vez liberado, la exposición constante al plomo en humanos puede ocasionar diversas enfermedades, incluyendo las que afectan el sistema nervioso central, y sobre todo diversos tipos de cáncer. Para que se desarrolle el cáncer se requiere que una célula normal esté expuesta a factores que promuevan cambios genéticos, epigenéticos y del microambiente, ocasionando la transformación e inmortalización celular. El objetivo de esta revisión es describir la importancia del plomo en el ambiente y sus consecuencias sobre la salud humana. Se realizó una búsqueda de artículos de años recientes relacionados con el plomo, medio ambiente y su relación con los efectos en el ser humano, incluyendo el cáncer. Se utilizaron las bases de datos PubMed, ResearchGate y Google Scholar, usando las palabras clave: plomo, lead, cancer, environmental pollution. En esta revisión reportamos los efectos del plomo en el desarrollo de enfermedades y del cáncer en el humano, además de la toxicidad de este metal.

Background/Objectives: Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. Methods: The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. Results:TIMP1 was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. TIMP2, TIMP3, and TIMP4 were downregulated in tumors. High expression of TIMP1 and TIMP4 correlated with better overall survival. TIMP1-associated genes were enriched in NF-kappa and PI3K–Akt signaling and actin cytoskeleton components. TIMP2 was linked to Hedgehog and MAPK pathways and actin-related elements. TIMP3 correlated with Hedgehog and PI3K–Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K–Akt, DNA damage pathways, and actin organization. TIMP2 showed strong positive correlations with MMP2 and MMP14, while TIMP4 showed negative correlations with MMP1 and MMP9. Interestingly, we found a strong positive correlation between TIMP2 and TIMP3 with ADAM12, as well as between TIMP2 and TIMP3 with ADAM10, and negative correlations with ADAM15. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. Conclusions: TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. TIMP1 emerges as the only consistently overexpressed inhibitor, while TIMP4 appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors.

Breast cancer is the most common and the leading cause of cancer death in women worldwide; treating invasive breast carcinomas is challenging due to the side effects of chemotherapeutics. Compounds isolated from natural sources have been proposed as potential molecules for cancer therapy; for instance, the homoisoflavonoid brazilin has shown pharmacological properties, including anti-tumoral and anti-inflammatory activities. In this study, we isolated brazilin from the heartwood of Haematoxylum brasiletto (Pacific coast of Mexico and Central America); then, we performed a semi-synthesis by adding three methyl or acetyl groups to the core structure of brazilin. We confirmed brazilin and its derivatives identity by spectroscopic data (1H NMR and 13C NMR) and measured their purity by optical rotation. Then, we analyzed the effects of brazilin and derivatives in three mammary gland-derived cell lines: the TNBC MDA-MB-231, the ER(+) MCF7, and the non-tumorigenic MCF10A. We evaluated the cell viability by MTT assays, cell migration by wound-healing assays and focal adhesion kinase (FAK) activation by Western blot. Regarding biological assays, the MTT assay showed that brazilin and its derivatives showed cytotoxic effects on MCF7 and MDA-MB-231 breast cancer cells at 20 µM but was not toxic in non-tumorigenic MCF10A mammary epithelial cells. These effects were dose and time-dependent, as well as a decrease in the levels of cell migration and FAK activation.