Palladium-catalyzed cross-coupling reactions of propargylic electrophiles with carbon nucleophiles have been established as straightforward and reliable methods for the synthesis of allenes and 1,5-enynes. However, such transformations have so far been limited to two-component systems. Herein, we report a palladium-catalyzed three-component coupling reaction involving bromoalkynes, diazoesters, and boronates. The reaction proceeds via allenylpalladium or propargylpalladium intermediates, generated through a sequence of oxidative addition, carbene formation, and migratory insertion upon interaction of haloalkynes with diazo compounds under palladium catalysis. Depending on the structure of the boronate substrate, the three-component coupling selectively delivers either allenes or 1,5-enynes. DFT calculations provide insight into this substrate-dependent chemoselectivity. The method exhibits broad substrate scope and has been successfully applied to the concise synthesis of two pharmaceutical agents-aminoglutethimide and anileridine.

To investigate the need for an ovarian-specific steroidogenesis assay in regulatory testing, steroid hormone profiles from adrenal H295R and ovarian KGN and COV434 cell cultures were compared with primary human cultures using LC-MS/MS. Hierarchical clustering showed close similarity between steroid hormone profiles of H295R and human fetal adrenal and ovarian tissue cultures, while KGN and COV434-derived profiles closer resembled human adult ovarian profiles. COV434 cultures showed the lowest number of steroid hormones even after forskolin stimulation. Specifically, in vehicle-treated controls 17 out of 21 steroid hormones were quantified in H295R cultures, 10 in KGN cultures and 7 in COV434 cultures. These included three backdoor pathway steroids, which were detected in different levels in the three cell cultures. Reference chemicals for steroidogenic disruption showed different effects in the cell lines, with most striking results early in the steroidogenic pathway. Atrazine, ketoconazole and aminoglutethimide affected pregnenolone and progesterone concentrations in KGN cultures more potently than in H295R cultures. Ketoconazole and propylparaben increased progesterone levels in H295R, but decreased levels in KGN cultures. Despite the differences in responses, classification of the test chemicals to act as steroidogenic disruptors was similar in H295R and KGN cell lines, but only when the OECD criteria were applied to a broad steroidome. These data do not support the use of KGN cells as an ovarian-specific steroidogenesis assay in a regulatory context, but do support the inclusion of more steroid hormones in the current test guideline to enhance the information that can be retrieved from the H295R assay.

Cushing's syndrome is one of the most common endocrine disorders in dogs and is typically managed with long-term medical treatment. Several pharmacological agents are available: trilostane, mitotane, ketoconazole, cabergoline, selegiline, and aminoglutethimide, but their comparative effects on survival remain unclear. This systematic review and meta-analysis compared the impact of these agents on survival outcomes in dogs with naturally occurring diseases. A comprehensive search of MEDLINE, Embase, Web of Science, Academic Search Complete, and the Cochrane Library was conducted between 1 September 2024 to 3 January 2025. Eligible studies included dogs diagnosed with Cushing's syndrome that reported survival outcomes for at least one of the specified treatments. Five studies (n = 295 dogs) met the inclusion criteria, with trilostane and mitotane providing sufficient data for meta-analysis. Pooled mean difference in survival time across four studies was 85.1 days (95% CI: -255.9 to 85.7, p = 0.21) with substantial heterogeneity (I[2] = 89%), indicating no statistically significant difference between the drugs. In contrast, pooled survival rates at fixed intervals favored trilostane, with an 11% higher survival at 36 months (p = 0.005) and no heterogeneity observed (I[2] = 0%). These findings suggest trilostane may offer long-term survival benefits over mitotane.

Substituted piperidine-2,6-diones are privileged scaffolds in numerous bioactive molecules and their facile and practical preparation still remains unsolved. In this paper, a facile and practical approach for the construction of α-substituted and α,α-/α,β-disubstituted piperidine-2,6-diones from abundant methyl acetates and acrylamides under transition-metal free condition was disclosed. It features mild reaction condition, operational simplicity, and excellent functional group tolerance, delivering a wide range of piperidine-2,6-diones in moderate to good yield. Furthermore, the application potential was further demonstrated by reaction scale-up (5 kilo-gram scale) and bio-active molecule synthesis (Aminoglutethimide and Niraparib). Additional control experiments revealed that the radical process could be excluded from this reaction and a michael addition/intramolecular imidation cascade sequence was proposed based on the control experiments. All these results demonstrated its significant application potential both in academic and industrial production.

Idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH) are two chronic conditions that can coexist occasionally, resulting in high morbidity and mortality. Despite their clinical association, the underlying genetic mechanisms and therapeutic targets that might link these two chronic disorders remain poorly understood. The present study used in silico analyses and machine learning to uncover genetic features and potential therapeutic targets shared by IPF and PH. Differentially expressed genes (DEGs) were identified using RNA sequencing data from the Gene Expression Omnibus, which revealed a total of 13 common DEGs between IPF and PH. Importantly, among the identified genes, TFF3 was significantly upregulated in both diseases. TFF3 is targeted by aminoglutethimide as identified through the Drug Gene Interaction Database, and with an interaction score of 3.26. Using the Protein Contact Atlas, PROCHECK, PROSA, and ProtParam tools, the structural model of TFF3 was validated. Finally, molecular docking analysis demonstrated a binding affinity score of -6.1 kcal/mol between TFF3 and aminoglutethimide, indicating a stable and potentially effective interaction between aminoglutethimide and the target protein. Aminoglutethimide displayed favorable ADMET properties as well. In conclusion, this in silico study reports (1) potential overlapping molecular links between IPF and PH, and (2) in silico potential of aminoglutethimide and TFF3 in drug repurposing for therapeutic interventions targeting both IPF and PH. These findings also challenge the traditional paradigm of pharmaceutical innovation that has long relied on the "one drug, one disease" premise, and highlight the potentials of "one drug, polydisease" paradigm of drug discovery and development.

Triple negative breast cancer (TNBC) has high recurrence and low survival rates among breast cancer types. So far, TNBC treatment has been limited to chemotherapy, which leads to high recurrence and drug resistance. The immune cells in the tumor microenvironment (TME) play an important role in tumor development and cancer progression. This study aimed to explore how immune cells in TME have been used to treat TNBC cases in combination with Doxorubicin (DOX). Searching was conducted for scientific publications on several databases in the past 10 years (2013-2023). Of the 7622 articles, 14 articles met the inclusion criteria and underwent the extraction process. All articles extracted in this review were preclinical studies on experimental animals. The results indicate the combination of DOX with cyclophosphamide and aminoglutethimide, increasing CD8 + infiltration resulting in tumor growth inhibition. The combination of DOX with vorinostat and molecular PepO also induces anti-tumor activity in the TME via increased infiltration of B cells and T cells and induced transition from M2 into M1. Other results, which lead to better prognosis have been obtained from the combination of DOX with losartan and anti-PD1 that leads to overhauling the immunosuppressive microenvironment. Targeting immune cells in TME such as dendritic cells, tumor-associated macrophages, CD8 + and CD4 + T cells are potentially used as therapeutic targets for TNBC treatment to optimize anti-tumor activity using combinations of DOX and certain drugs.

Copper (Cu) is an essential trace element for biological growth and development. Excessive intake of Cu exists harmful effects on organisms. However, whether excessive Cu intake induces kidney function damage by gut microbiota regulation remains unclear. Ducks are important species of waterfowl that are often exposed to Cu contamination in water sources. In this study, we aim to elucidate the effects of Cu exposure on renal inflammation through the gut-kidney axis in ducks. The ducks were gavaged with different doses of CuSO4 (0, 100, and 200 mg/kg body weight) for 4 weeks. Results indicate that Cu exposure causes pathological damage to the kidney, with a significant increase in the levels of TNFα, IL-6, and IL-1β in both serum and renal tissue. 16S rDNA analysis revealed that the relative abundances of Candidatus_Saccharimonas and Bacteroides were significantly reduced in the Cu-induced group. Transcriptomic analysis of kidney tissue reveals that following Cu exposure, 30 genes show significant differential expression. GO and KEGG enrichment analyses were most involved in Interleukin-1 Receptor Activity, Taurine and hypotaurine metabolism, Nitrogen metabolism, and Proximal tubule bicarbonate reclamation. Metabolomic analysis revealed that 28 metabolites are present in both kidney tissue and cecal contents. Correlation analysis revealed a strong correlation among 5 common metabolites: Aminoglutethimide, Boscalid, Dantrolene, Cer[ns] d34:1, and Stearidonic acid. In the cecum, these five metabolites are closely associated with 26 intestinal microorganisms, including Bacteroides, Candidatus_Saccharimonas, and Colidextribacter. In the kidney, apart from Stearidonic acid, the other four metabolites are closely correlated with genes such as FOS, and IL1RL1. Overall, our study indicates that excessive Cu induces significant kidney inflammation, the metabolites alteration and gut microbiota disorders. These findings shed light on the underlying mechanisms of Cu-induced kidney damage via the indirect pathway of the gut-kidney axis.

Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs.

Aim: We aim to develop new anti-leishmanial agents against Leishmania major and Leishmania tropica.Materials & methods: A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for in vitro activity against promastigotes of L. major and L. tropica.Results & conclusion: The N-benzoyl analogue 7p was found potent (IC50 = 12.7 μM) against L. major and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The N-hexyl compound 7v was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound 7r, with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against Leishmania, but was cytotoxic in nature. Compound 7v was thus identified as a hit for further studies.

Cells actively engaged in de novo steroidogenesis rely on an expansive intracellular network to efficiently transport cholesterol. The final link in the transport chain is STARD1, which transfers cholesterol to the enzyme complex that initiates steroidogenesis. However, the regulation of ovarian STARD1 is not fully characterized, and even less is known about the upstream cytosolic cholesterol transporters STARD4 and STARD6. Here, we identified both STARD4 and STARD6 mRNAs in the human ovary but only detected STARD4 protein since the primary STARD6 transcript turned out to be a splice variant. Corpora lutea contained the highest levels of STARD4 and STARD1 mRNA and STARD1 protein, while STARD4 protein was uniformly distributed across ovarian tissues. Cyclic AMP analog (8Br-cAMP) and phorbol ester (PMA) individually increased STARD1 and STARD4 mRNA along with STARD1 protein and its phosphoform in cultured primary human luteinized granulosa cells (hGCs). STARD6 transcripts and STARD4 protein were unresponsive to these stimuli. Combining lower doses of PMA and 8Br-cAMP blunted the 8Br-cAMP stimulation of STARD1 protein. Increasing cholesterol levels by blocking its conversion to steroid with aminoglutethimide or by adding LDL reduced the STARD4 mRNA response to stimuli. Sterol depletion reduced the STARD1 mRNA and protein response to PMA. These data support a possible role for STARD4, but not STARD6, in supplying cholesterol for steroidogenesis in the ovary. We demonstrate for the first time how cAMP, PMA and sterol pathways separately and in combination differentially regulate STARD4, STARD6 and STARD1 mRNA levels, as well as STARD1 and STARD4 protein in human primary ovarian cells.

Somatic mutations contribute to cancer development by altering the activity of enhancers. In the study, a total of 135 mutation-driven enhancers, which displayed significant chromatin accessibility changes, were identified as candidate risk factors for breast cancer (BRCA). Furthermore, we identified four mutation-driven enhancers as independent prognostic factors for BRCA subtypes. In Her2 subtype, enhancer G > C mutation was associated with poorer prognosis through influencing its potential target genes FBXW9, TRIR, and WDR83. We identified aminoglutethimide and quinpirole as candidate drugs targeting the mutated enhancer. In normal subtype, enhancer G > A mutation was associated with poorer prognosis through influencing its target genes ALOX15B, LINC00324, and MPDU1. We identified eight candidate drugs such as erastin, colforsin, and STOCK1N-35874 targeting the mutated enhancer. Our findings suggest that somatic mutations contribute to breast cancer subtype progression by altering enhancer activity, which could be potential candidates for cancer therapy.

Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In addition, an experimental study found that hexaconazole may disrupt the normal synthesis of steroidal hormones. The potency of hexaconazole to bind with sex hormone-binding globulin (SHBG), a plasma carrier protein that binds androgens and oestrogens, is unknown. In this study, we evaluated the efficacy of hexaconazole to bind with SHBG by molecular interaction, a molecular dynamics method. In addition, principal component analysis was performed to understand the dynamical behaviour of hexaconazole with SHBG in comparison with dihydrotestosterone and aminoglutethimide. The binding scores of hexaconazole, dihydrotestosterone, and aminoglutethimide with SHBG were found to be -7.12 kcal/mol, -11.41 kcal/mol, and -6.84 kcal/mol, respectively. With respect to stable molecular interaction, hexaconazole showed similar molecular dynamics patterns of root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and hydrogen bonding. The solvent surface area (SASA) and principal component analysis (PCA) of hexaconazole exhibit similar patterns in comparison with dihydrotestosterone and aminoglutethimide. These results show that hexaconazole has a stable molecular interaction with SHBG, which may acquire the active site of the native ligand, resulting in significant endocrine disruption during agricultural work.