Chemical Biology & Drug Design最新文献

Aberrant activation of the RAS/RAF/MEK/ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1/2 has crucial roles in tumorigenesis, cell proliferation, and inhibition of apoptosis. At present, a number of MEK1/2 inhibitors are approved for the treatment of melanoma. However, MEK1/2 inhibitors have poor single-drug efficacy in the treatment of solid tumors and are prone to drug resistance. A series of compounds containing a diarylamine skeleton and phenylacrylamide (acrylamide) have been designed and synthesized in this paper. The most promising compound M15 showed good inhibitory activity of MEK1 (IC₅₀ = 10.29 nM) and good inhibitory effect on three types of solid tumor cells: MDA-MB-231(IC₅₀ = 2.76 μM), HepG2 (IC₅₀ = 2.57 μM) and A549 (IC₅₀ = 5.40 μM). At the same time, M15 was less toxic to human normal cells (MCF-10A IC₅₀ > 20 μM) and has certain stability of liver microsomes in vitro (human, t_1/2 = 27.9 min; rat, t_1/2 > 60 min). It can induce apoptosis of MDA-MB-231 cells and slow down their migration. Therefore, compound M15 acts as a novel MEK1/2 inhibitor and may be a promising candidate for solid tumor intervention.

Increased HER2 expression during breast cancer and its metastatic spread can be checked by specific probes having high affinity towards the target. This study aimed at developing ^99mTc-labelled HER2-specific molecular probe for accurate detection. The two rL-A9 peptide variants, HYNIC-rL-A9 and HYNIC-PEG₁₂-rL-A9 were manually synthesized by solid phase methodology. ^99mTc-labelling of peptides was accomplished using EDDA and tricine as co-ligands. [^99mTc]Tc-HYNIC-rL-A9 showed poor uptake in HER2-expressing human breast carcinoma SKBR3 cells whereas the PEGylated counterpart [^99mTc]Tc-HYNIC-PEG₁₂-rL-A9 demonstrated high specific cellular uptake (3.01% ± 0.14%) and low nanomolar binding affinity (K_d = 17.11 ± 7.63 nM). Tumour uptake (SKBR3) of [^99mTc]Tc-HYNIC-PEG₁₂-rL-A9 was higher at 1 and 3 h in comparison to the non-PEGylated radiopeptide. Blocking studies led to 70% reduction in accumulation of radioactivity in the tumour indicating specificity of the radiopeptide. Introduction of polyethylene glycol (PEG₁₂) as pharmacokinetic modifier led to significantly improved biological profile of the [^99mTc]Tc-HYNIC-labelled rL-A9 peptide conjugate.

Tropical parasitic diseases like leishmaniasis pose significant public health challenges, impacting millions of individuals globally. Current drug treatments for these diseases have notable drawbacks and side effects, underscoring the pressing need for new medications with improved selectivity and reduced toxicity. Through structural modifications of both natural and synthetic compounds using click chemistry, researchers have been able to produce derivatives showing promising activity against these parasites. In this study, 21 novel 1,2,3-triazole analogues of totarol were synthesized using O-propargylated totarol derivatives and substituted arylazide. These compounds were characterized through various analytical techniques, including ¹H NMR, ¹³C NMR, and HRMS. An x-ray crystallographic study of compounds 4 and 6 was carried out to fully establish the structure of the newly prepared totarol derivatives. All synthesized compounds were then screened in vitro for their antileishmanial activities against Leishmania major promastigotes, amastigotes, and Toxoplasma gondii tachyzoites Out of the tested analogues, six compounds (7c, 8b–e, and 9 g) displayed antileishmanial activity against L. major amastigotes with IC₅₀ 17.3, 14.2, 13.1 18.2 13.2 and 17.3 μg mL⁻¹ respectively, while only 8e gave antileishmanial activity against both promastigotes and amastigotes with IC₅₀ 11.7 and 13.2 μg mL⁻¹ respectively. Additionally, the presence of a nitro group was correlated with enhanced antileishmanial activity. Moreover, a molecular docking study was conducted, focusing on 8e, the most active antileishmanial compound, to elucidate its putative binding pattern at the active site of the selected leishmanial trypanothione reductase target.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis. Baicalein, a natural compound, can regulate multiple cellular processes in various cancer types. In this study, we investigated the role of baicalein in regulating HCC and explored its potential mechanism. The expression of mediator complex subunit 7 (MED7) and E2F transcription factor 1 (E2F1) was analyzed by quantitative real-time polymerase chain reaction or Western blotting assay. Cell proliferation was assessed by cell colony formation assay and 5-ethynyl-2′-deoxyuridine assay. Cell migration was analyzed by transwell assay and wound-healing assay. Cell invasion was analyzed by transwell assay. Angiogenic ability of HCC cells was assessed by tube formation assay. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to validate the association between E2F1 and MED7. The xenograft mouse model assay was conducted to determine the effects of baicalein and E2F1 overexpression on tumor formation. Immunohistochemistry assay was used to determine positive expression rates of proteins. Upregulation of MED7 and E2F1 expression was observed in both HCC tissues and cells. Knockdown of MED7 suppressed HCC cell proliferation, migration, invasion, and tube formation. Transcriptional activation of MED7 by E2F1 was demonstrated in HCC cells. Overexpression of MED7 mitigated the effects induced by E2F1 depletion in HCC cells. Additionally, baicalein treatment effectively inhibited the tumor property of HCC cells by decreasing E2F1 expression in both in vitro and in vivo models. Baicalein inhibited the tumor property of HCC cells through the inactivation of the E2F1/MED7 axis, highlighting its potential clinical application in the treatment of HCC.

Mesangial proliferative glomerulonephritis (MsPGN) is a common type of glomerular disease characterized by immune complex deposition and inflammation in the kidney, leading to renal dysfunction. Currently, treatment options for MsPGN are limited, and there is a need for effective therapeutic interventions. Hesperidin (HSP), a natural flavonoid glycoside, has shown promising anti-inflammatory and antioxidant properties in various disease models. This study aimed to investigate the therapeutic potential of HSP for MsPGN and explore its possible mechanism of action. A male Wistar rat model of MsPGN was established via tail vein injection of Thy-1 monoclonal antibody, and the rats were divided into four groups: Control, MsPGN, MsPGN + HSP, and MsPGN + Prednisone. After 7 days of intervention, the therapeutic effects of HSP were evaluated through biochemical and histological analyses. Our results demonstrated that HSP treatment significantly reduced the levels of blood urea nitrogen, serum creatinine, total cholesterol, and triglycerides, and improved renal pathology. Additionally, pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-2, and monocyte chemoattractant protein-1, were markedly decreased. Immunofluorescence analysis revealed reduced levels of immunoglobulin G and C5b-9, along with decreased immune complex deposition in the kidneys. Furthermore, HSP downregulated the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), suggesting modulation of the JAK/STAT pathway. In conclusion, HSP might effectively alleviate renal injury, reduce renal inflammatory response, and inhibit renal immune complex deposition, potentially through the suppression of the JAK/STAT pathway.

Despite advancements in molecular design rules and understanding biochemical processes, the field of drug design and discovery seeks to minimize the number and duration of synthesis-testing cycles to convert lead compounds into drug candidates. A promising strategy involves gaining insightful understanding of key heteroatoms such as oxygen and nitrogen. This work presents a comprehensive analysis of oxygen atoms in approved drugs, aiming to streamline drug design and discovery efforts. The study examines the frequency, distribution, prevalence, and diversity of oxygen atoms in a dataset of 2049 small molecules approved by the FDA and other agencies. The analysis focuses on various types of oxygen atoms, including sp³, sp²-hybridized, ring, and nonring. In general, existence of sp³-O slightly outperforms sp²-O, which is associated with balancing various factors such as flexibility, solubility, stability, and pharmacokinetics, in addition to activity and selectivity. In approved drugs, majority of oxygen atoms are present within 4 Å from the COM of the molecule. This analysis offers valuable understanding of oxygen distribution, which could be used during the multiparameter optimization process, facilitating the transformation of a hit/lead compound into a potential drug candidate.

Luteolin and quercetin, which are flavonoids, are present in various traditional Chinese medicines. Although they have been shown to improve obesity, the specific mechanisms of action remain unclear. This study aimed to determine pivotal targets and major regulatory pathways involved in their mechanisms of action using network pharmacology and transcriptome sequencing. Data on luteolin/quercetin-related targets were acquired from the PharmMapper platform, and data on known obesity-related targets were collected from the OMIM and GeneCards databases. Differentially expressed genes (DEGs) involved in luteolin and quercetin action that regulate adipogenic differentiation were identified using RNA sequencing (RNA-seq). Bioinformatic analyses were performed to identify potential target genes and pathways regulated by luteolin/quercetin during adipogenesis. Finally, key genes and pathways were validated through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Network pharmacology showed that luteolin/quercetin was closely associated with anti-obesity targets. The related pathways were metabolic, PI3K/AKT, and MAPK pathways. RNA-seq revealed 91 common DEGs involved in luteolin/quercetin regulation of adipogenic differentiation. Finally, nine potential target genes (including CIDEC, Mgll, Slc2a4, Pck1, and PNPLA3) were identified, and the AMPK and AKT signaling pathways were verified. The present study provides novel information regarding the molecular mechanism of luteolin and quercetin action in treating obesity and demonstrates their therapeutic effects through multiple targets and pathways.

Cardiovascular diseases (CVDs) continue to be one of the leading causes of morbidity and mortality worldwide, with a significant increase in recent years. Atherosclerosis, the pathological basis and prime reason for CVDs is primarily driven by dysregulated lipid metabolism and inflammation. Recently, proprotein convertase subtilisin kexin9 (PCSK9) has been evolved to be highly implicated in the circulatory low-density lipoprotein cholesterol levels by its modulatory effects on the low-density lipoprotein receptor (LDLR) mediated clearance. Even though not economical, the therapies targeting PCSK9 demonstrated appreciable levels of efficiency in managing hyperlipidaemic conditions. Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is a naturally occurring para-benzoquinone isolated from dried berries of Embelia ribes, which possess several effects in maintaining the cholesterol homeostasis. In this study, we have analysed the role of embelin in sterol regulatory element-binding protein 2 (SREBP2) mediated PCSK9 expression in cultured hepatocytes. The study showed that the embelin treatment attenuates the endoplasmic reticulum (ER) stress-induced reactive oxygen species levels and ER stress markers on cultured hepatocytes. The treatment of embelin modulates the mRNA and protein level expression of SREBP2 and its downstream targets like PCSK9, LDLR, and HMG-CoA reductase (HMGCR). Interestingly the Ca2+ levels and the calcium binding protein of ER were significantly increased with embelin treatment. The work revealed a putative mechanism of embelin in lowering PCSK9 levels by boosting ER Ca2+ levels, thereby blocking SREBP2 nuclear translocation. Further, this reduces LDLR degradation and increases receptor-mediated circulatory lipid clearance. The study summarized the potential clinical applications of embelin in addressing the cardio vascular diseases.

PTP-PEST (also known as PTPN12) regulates cellular signaling and transduction pathways by dephosphorylating its substrate. PTP-PEST is considered an important drug target owing to its involvement in cancer progression and myocardial injury. Till now only a few inhibitors are currently being studied in the inhibition of PTP-PEST, majorly belonging to the class of metal-based drugs. In this study, we aimed to investigate small molecules that could potentially inhibit PTP-PEST for further development of PTP-PEST inhibitors. As an approach, we used an in silico molecular docking technique to screen an in-house synthesized molecular library. Further, we validated the docking results by in vitro inhibition screening of the best molecules using the purified catalytic domain of human PTP-PEST, which was over-expressed in E.coli. We identified a myo-inositol based derivative, J1-65, which binds to PTP-PEST and results in the competitive inhibition of the protein. Further, we confirmed this protein-ligand binding using binding affinity studies based on protein thermal shift assay and in silico molecular dynamic simulations. Our efforts to discover a novel scaffold for inhibiting hPTP-PEST mark a crucial stride in laying the groundwork for the future development of selective PTP-PEST inhibitors.