Chemical biology & drug design最新文献

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC₅₀ = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.

The present study was to investigate the underlying mechanism of the antitumor effect of curcumin in colorectal cancer cells, focusing on the M2 polarization of tumor-associated macrophages (TAMs). The effect of curcumin on the malignant behavior of colorectal cancer cells was investigated by WST assay for cell growth, and Transwell assay for cell migration/invasion. THP-1 cells were differentiated into macrophages and coculture with colorectal cancer cells to study the influence of curcumin on M2 polarization, presenting as the levels of ARG1 mRNA, IL-10, and CD163-positive cells. GEO database was searched for the shared altered gene of curcumin in colorectal cells and human monocytes. Molecular docking was used to visualize the binding between curcumin and MACC1. Curcumin restricted the proliferation, apoptosis, and migration/invasion of HCT 116 and SW620 cells. Curcumin attenuated levels of the M2 macrophage markers, CD163 + cells, IL-10 secretion, and ARG1 mRNA. MACC1 was a target of curcumin in colorectal cancer cells, relating to macrophage. Rescue experiments showed that MACC1 overexpression can reverse the antitumor effect of curcumin in colorectal cancer cells and M2 polarization of TAMs. Curcumin's antiproliferative and anti-migratory effects in colorectal cancer cells may be mediated by MACC1 and inhibition of M2 polarization of TAMs.

KeChuanLiuWei-Mixture (KCLW) is widely used as a Chinese medicine prescription to treat severe asthma. However, the underlying therapeutic mechanism of KCLW remains unclear. In this study, a network pharmacology method was used to identify the chemical constituents of KCLW by the TCMSP database and ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry. Differential expression identification, protein–protein interaction (PPI) network and functional enrichment analysis were used to screen key targets of KCLW for severe asthma. Our results confirmed that quercetin, luteolin, kaempferol, and wogonin are the most critical active ingredients in KCLW. Moreover, the 16 relevant severe asthma-related targets of KCLW were obtained by overlapping the PPI networks of the KCLW putative targets and severe asthma-related genes, among which the most important targets were IL-6, NOS2, VEGFA, CXCL2, and PLAT. Functionally, the 16-targets and their interacting differentially expressed genes were primarily related to biological functions and pathways related to immunity and inflammation, such as inflammatory response, T cell differentiation, Nrf2/HO-1 signaling pathway, TGF-β/Smad signaling pathway, and NF-κB signaling pathway. KCLW inhibited inflammation in PDGF-BB-induced airway smooth muscle cells. In summary, this study demonstrates the active substance and potential therapeutic mechanism of KCLW in severe asthma, and offers a clinical direction for KCLW against severe asthma.

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol⁻¹ below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular H^…O hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that shows high metastatic capability and poor prognosis. The aggressive behavior of TNBC may involve amplified EGFR expression. Currently, no targeted therapy has been approved for treating TNBC, which urgently needs novel treatment options. In this study, we report that estrone analogs with novel pharmacophores exhibited high potency toward TNBC cells through multiple mechanisms, inhibition of cell proliferation via EGFR receptor, and induction of mitochondrial apoptosis. Molecular docking studies revealed that hit analogs MMA307 and MMA321 were potent against the EGFR receptor (pdb code: 1M17) in silico and were over 10-fold more potent than sorafenib (positive control) when dosed against MDA-MB-468 cells in vitro. MMA307 and MMA321 induced mitochondrial apoptosis as characterized by condensed nuclei with fragmented chromatin, phosphatidylserine flip and modulated expressions of Apaf1, cytochrome c, and caspases 3 and 9. MMA307 and MMA321 inhibited TNBC proliferation through suppression of EGFR and activated EGFR (Y1068) expressions. Similarly, EGFR signaling pathways, RAF/ERK and AKT/mTOR, were inhibited as pARaf, pERK1/2 (characterizes RAF/ERK pathway) and pAKT, pmTOR, p70S6Kα (characterizes AKT/mTOR pathway) were all suppressed. Moreover, MMA307 and MMA321 inhibited TNBC cell growth through downregulation of cyclin D1 expression and arresting TNBC cells in the G₁ phase of cell cycle. This study reports for the first time that estrone congeners with novel pharmacophores may be an effective therapy for TNBC. Findings from this research provide a solid foundation for further preclinical and clinical studies in developing estrone derivatives as novel TNBC therapeutics.

The small molecule, isatin, is a well-known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC₅₀ values of 12.3 and 4.86 μM for MAO-A and MAO-B, respectively. While the interaction of isatin with MAO-B has been characterized, only a few studies have explored structure–activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO-A and MAO-B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC₅₀ < 1 μM. 4-Chloroisatin (1b) and 5-bromoisatin (1f) were the most potent inhibitors with IC₅₀ values of 0.812 and 0.125 μM for MAO-A and MAO-B, respectively. These compounds were also found to be competitive inhibitors of MAO-A and MAO-B with K_i values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5-substitution was particularly beneficial for MAO-B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.

Praeruptorin A (PA), a natural coumarin compound, has significant anti-inflammatory effects. In this study, we evaluate the anti-inflammatory effect of PA on RAW 264.7 mouse macrophages induced by Polyinosinic acid-polycytidylic acid (poly (I:C)). RAW 264.7 mouse macrophages induced by poly (I:C) were treated with or without PA, the viability of which was determined to screen working solution of PA. RNA-sequencing was applied to analyze the differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were carried out. The expressions of interleukin (IL)-1β, heme oxygenase 1 (HMOX1), prostaglandin-endoperoxide synthase 2 (PTGS2), ATP binding cassette subfamily A member 1 (Abca1) and NF-κB-related proteins were measured by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. As a result, PA at 1, 2, 3, 4 and 5 μM slightly affected cell viability, while PA at 6 and 7 μM significantly inhibited cell viability. GO and KEGG analysis results revealed that DEGs were mainly enriched in the pathways related to inflammatory signaling. Through further analysis, we obtained five possible targets of PA, and verified that PA inhibited the expressions of IL-1β, HMOX1, PTGS2 and Abca1 as well as the activation of NF-κB pathway in poly (I:C)-induced RAW264.7 cells. To summarize, PA may inhibit expressions of the inflammation-related genes in poly (I:C)-induced RAW264.7 cells, which demonstrates its potential as a drug against virus related diseases.

In recent years, there has been a lot of buzz about the possibilities of marine microflora as a source of new therapeutic drugs. The strong anti-tumor potency of compounds found in marine resources reflects the ocean's enormous potential as a source of anticancer therapeutics. In this present investigation, an ambuic acid derivative anticancer compound was isolated from Talaromyces flavus, and its cytotoxicity and apoptosis induction potential were analyzed. T. flavus was identified through morphological and molecular analysis. The various organic solvent extracts of T. flavus grown on different growth mediums were evaluated for cytotoxicity on different cancer cell lines. The potent cytotoxicity was shown in the ethyl acetate extract of a fungal culture grown in the M1-D medium for 21 days. Furthermore, the anticancer compound was identified using preparative thin layer chromatography, followed by its purification in significant proportions using column chromatography. The spectroscopic and chromatographic analysis revealed that the structure of the purified molecules was an ambuic acid derivative. The ambuic acid derivative compound showed potent cytotoxicity on MDA-MB-231 (breast cancer cells) with an IC₅₀ value of 26 μM and induced apoptosis in the MDA-MB-231 cells in a time-dependent and reactive oxygen species-independent manner.