Chemical Biology & Drug Design最新文献

Paeoniflorin (PF) is one of the active constituents of the traditional Chinese medicine Paeoniae Radix Rubra and has been actively explored in the pharmaceutical area due to its numerous pharmacological effects. However, severe difficulties such as limited bioavailability and low permeability limit its utilization. Therefore, this study developed and synthesized 25 derivatives of PF, characterized them by ¹H NMR, ¹³C NMR, and HR-MS, and evaluated their antioxidant activity. Firstly, the antioxidant capacity of PF derivatives was investigated through DPPH radical scavenging experiment, ABTS radical scavenging experiment, reducing ability experiment, and O₂^.− radical scavenging experiment. PC12 cells are routinely used to evaluate the antioxidant activity of medicines, therefore we utilize it to establish a cellular model of oxidative stress. Among all derivatives, compound 22 demonstrates high DPPH radical scavenging capacity, ABTS radical scavenging ability, reduction ability, and O₂^.− radical scavenging ability. The results of cell tests reveal that compound 22 has a non-toxic effect on PC12 cells and a protective effect on H₂O₂-induced oxidative stress models. This might be due to the introduction of 2, 5-difluorobenzene sulfonate group in PF, which helps in scavenging free radicals under oxidative stress. Western blot and molecular docking indicated that compound 22 may exert antioxidant activity by activating Nrf2 protein expression. As noted in the study, compound 22 has the potential to be a novel antioxidant.

To combine the activity characteristics of 18β-glycyrrhetinic acid (18β-GA) and anthraquinone compounds (rhein and emodin), reduce toxicity, and explore the structure–activity relationship (SAR) of anthraquinones, 18β-GA-anthraquinone ester compounds were synthesized by one-step organic synthesis. The products were separated and purified by HPLC and characterized by NMR and EI-MS. It was finally determined as di-18β-GA-3-rhein ester (1, New), GA dimer (2, known), 18β-GA-3-emodin ester (3, known), and di-18β-GA-1-emodin ester (4, new). The MIC of three reactants and four products against Escherichia coli and Staphylococcus aureus were detected in vitro. Its developmental toxicity and cardiotoxicity were assessed using zebrafish embryos. The experimental results showed that rhein had the best antibacterial activity against Staphylococcus aureus with MIC₅₀ of 2.4 mM, and it was speculated that –COOH, –OH, and intramolecular hydrogen bonds in anthraquinone compounds would enhance the antibacterial effect, while the presence of-CH₃ might weaken the antibacterial activity. Product 1 increased the hatching rate and survival rate of zebrafish embryos and reduced the malformation rate and cardiomyocyte apoptosis. This experiment lays the foundation for further studying the SAR of anthraquinones and providing new drug candidates.

Breast cancer (BC) is one of the leading causes of high mortality rates in women worldwide. Although advancements have been made in the design of therapeutic strategies and drug discovery, drug resistance remains one of the key challenges. One of the ways to overcome drug resistance is finding potential drug combinations since the efficacy of combined drugs is higher than their individual efficacies if the combination is a synergistic pair. Therefore, the current study uses a BC patient-derived xenograft (PDX) dataset to evaluate the effects of various cancer drugs on breast cancer in vivo models. The drug effects are further validated by four machine learning models, namely Elastic Net, Least Absolute Shrinkage and Selection (LASSO), Support Vector Machine (SVM), Random Forests (RF), as well as exploring the shortlisted drugs in combination with paclitaxel, a baseline drug for enhanced efficacy on tumor volume reduction. Additionally, the study also shortlists the top 50 in vivo biomarkers correlated with the effects of the drugs. The outcomes could be significantly important for the design of an effective anti-breast cancer therapy.

This research investigated the preventive effects of myrtenol (MYR), fatty acid nanocarriers (FANC), and myrtenol-loaded FANC (MYR + FANC) on neurological disturbance, stroke volume, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and tumor necrosis factor-alpha (TNF-α) in the brain with ischemia–reperfusion injuries induced by middle cerebral artery occlusion (MCAO) in rats. Seventy two Wistar male rats were divided into six main groups. The groups were sham, ischemia–reperfusion group (MACO), MACO-MYR (50 mg/kg), MACO-FANC (50 and 100 mg/kg), and MACO-MYR + FANC (50 mg/kg). Stroke volume, neurological deficit scores, and the brain levels of MDA, SOD, and TNF-α were examined with TTC staining, observation, and ELISA, respectively. Pretreatment with MYR, FANC (100 mg/kg), and MYR + FANC reduced the neurological deficit score and cerebral infarction volume. MYR, FANC (100 mg/kg), and MYR + FANC pretreatment increased and decreased brain SOD and MDA levels compared to MACO group, respectively. The TNF-α level decreased in the MYR + FANC group compared to MCAO and MCAO-MYR groups in the brain. The use of FANC (100 mg/kg), MYR, and MYR + FANC has protective effects against oxidative stress and ischemia–reperfusion injury. FANC probably improve the bioavailability of MYR, as MYR+ FANC had more therapeutic effects on the reduction of ischemia–reperfusion injuries, inflammation, and oxidative stress.

This study aimed to investigate the effects of the monoterpenes thymol and p-cymene on the liver of rats subjected to prolonged immobilization stress and to discover the possible mechanism behind this effect. For 14 consecutive days, the rats were placed in a restrainer for 2.5 h every day to expose them to stress. During the same period, thymol (10 mg/kg, gavage) and p-cymene (50 mg/kg, intraperitoneally) were also administered. Thymol and p-cymene prevented the increase in malondialdehyde levels and the decrease in glutathione content in the liver of rats exposed to chronic immobility. They also increased the activity of the glutathione peroxidase enzyme in the liver of stressed animals, but only thymol could increase the activity of superoxide dismutase. These monoterpenes reduced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 and nuclear factor kappa B (NF-κB) in the liver of stressed animals. They increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Thymol and p-cymene greatly prevented the infiltration of inflammatory cells in the liver parenchyma of stressed rats. In conclusion, the study found that thymol and p-cymene have a hepatoprotective effect on immobilized rats, likely exerted by suppressing oxidative stress and inflammation, stimulating Nrf2/HO-1 signaling, and inhibiting the TNF-α/NF-κB pathway.

In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1β,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI₅₀ in range of 1.2–15.4 μM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.

Diabetes Mellitus (DM) is linked to various factors causing cardiovascular diseases, with uncontrolled postprandial hyperglycemia being a direct contributor. α-Glucosidase inhibitors (AGIs) aid in reducing postprandial hyperglycemia, potentially mitigating cardiovascular risks. In order to synthesize novel chemical scaffolds with possible α-glucosidase inhibition activity, a series of novel soritin sulfonamide derivatives were synthesized. The soritin hydrazide was treated with various aryl sulfonyl chlorides to obtain targeted compounds (1–16). Findings suggested that all compounds have better α-glucosidase inhibition compared to standard drugs, acarbose (2187.00 ± 1.25 μM) and 1-deoxynojirimycin (334.90 ± 1.10 μM), with IC₅₀ values ranging from 3.81 ± 1.67 μM to 265.40 ± 1.58 μM. The most potent analog was Compound 13, a trichloro phenyl substituted compound, with IC₅₀ value of 3.81 ± 1.67 μM. Structure–activity relationship (SAR) showed that introducing an additional chlorine group into the parent nucleus increases the potency. The docking studies validated that Compound 13 established hydrogen bonds with the active site residues Asp214, Glu276, and Asp349, while being further stabilized by hydrophobic interactions, providing an explanation for its high potency.