Novel curcumin derivatives N17 exert anti-cancer effects through the CSNK1G3/AKT axis in triple-negative breast cancer.

Curcumin, extracted from Zingiberaceae and Araceae rhizomes, is clinically used for its anti-inflammatory, antibacterial, antioxidant, and anti-cancer properties. Its safety and potential make it a promising base for designing enhanced derivatives. The focus now is on optimizing curcumin and synthesizing more potent 1,4-pentadien-3-ones, which have anti-cancer activities. In the realm of triple-negative breast cancer (TNBC), an aggressive and invasive form with high metastatic potential, the need for innovative treatments is acute. The challenges posed by chemotherapy resistance, recurrence, and TNBC's heterogeneity have emphasized the necessity for novel therapeutic approaches. Our strategy involved the integration of a quinoxaline ring into 1,4-pentadien-3-one, followed by subsequent modifications. In this study, N17 demonstrated the ability to induce cell death and effectively suppress cell proliferation in breast cancer cells. These observed anti-cancer effects were attributed to the inhibition of p-AKT(S473), a key regulator implicated in both cell apoptosis and the modulation of epithelial-mesenchymal transition process in breast cancer cells. Furthermore, our investigation indicated N17 achieves its inhibitory effects on p-AKT(S473) by specifically targeting the CSNK1G3 protein. Remarkably, N17 not only impedes the EMT process but also triggers apoptosis through the CSNK1G3/AKT signaling axis. These findings provide the critical role of CSNK1G3 as an anti-cancer regulator in TNBC, establishing N17 as a pharmacological intervention with immense promise for treating cancer metastasis.

A Novel Myricetin Derivative with Anti-cancer Properties Induces Cell Cycle Arrest and Apoptosis in A549 Cells.

Lung cancer is the leading cause of cancer-related deaths worldwide, synthesizing and screening of novel anti-cancer drugs provides an alternative therapeutic strategy for renewal of the chemotherapy regimens against lung cancer. To this end, several compounds were synthesized based on the modification of the original myricetin, and their anti-tumor activity against the human non-small cell lung cancer (NSCLC) A549 cells were measured. Among the myricetin derivatives, S4-10 has displayed the highest antitumor efficacy in dose-dependent manner. The proliferation of A549 cells were significantly attenuated by given 6 µM of S4-10 both in vitro and in vivo. Further, the treatment of S4-10 also results in the inhibition of cell migration and invasiveness and the induction of cell apoptosis and G2 cycle arrest of A549 cells. Moreover, we found that S4-10 inhibits the progression of A549 cells through the sterol biosynthetic-cell apoptosis axis. These findings shed the light of developing S4-10 as a promising treatment agent for NSCLC.

Novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments: Design, synthesis and bioactivity.

A series of novel penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether moieties were designed and synthesized. Their anticancer activities were evaluated by MTT assay, the results showed that most compounds exhibited extremely inhibitory effects against hepatoma SMMC-7721 cells. In particular, compounds Q2 and Q8 displayed the more potent inhibitory activity with IC50 values of 0.64 and 0.63 µM, which were better than that of gemcitabine (1.40 µM). Further mechanism studies indicated that compounds Q2, Q8, Q13 and Q19 could control the migration of SMMC-7721 cells effectively, and inhibit the proliferation of cancer cells by inhibiting the DNA replication. Western-blot results showed that compounds Q2 and Q8 induced irreversible apoptosis of SMMC-7721 cells by regulating the expression level of apoptose-related proteins. Those studies demonstrated that the penta-1,4-diene-3-one derivatives containing quinazoline and oxime ether fragments merited further research as potential anticancer agents.

3-(4-methoxyl)-1-(2-(4-coumarin)prop)-2-en-1-one inhibits the differentiation of Gaoyou duck embryonic osteoclasts in vitro.

This study determined the influence of 3-(4-methoxyl)-1-(2-(4-coumarin)prop)-2-en-1-one (MCPEO) on the differentiation of Gaoyou duck embryo osteoclasts cultured in vitro. Bone marrow mononuclear cells (BM-MNCs) were harvested from 23-day-old Gaoyou duck embryos and induced by receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of MCPEO at different concentrations (i.e., 1, 5, 10, 20, and 40 µM). Cell viability measurement, tartrate-resistant acid phosphatase (TRAP) staining, resorption activity assay, and co-staining with Tetramethylrhodamine (TRITC)-conjugated phalloidin and Hoechst 33,258 were conducted. Results indicated that MCPEO influenced the cell viability of the M-CSF + RANKL-induced BM-MNCs in a concentration-dependent manner, reduced the formation of positive multinucleated cells, and restrained the resorption capability of osteoclasts. Microfilament and nuclear staining indicated that MCPEO restricted the differentiation of BM-MNCs into large multinucleated osteoclasts. In short, MCPEO can inhibit the differentiation of BM-MNCs into mature osteoclasts in duck embryos. Therefore, MCPEO is a promising agent for the treatment of poultry osteoporosis.

Synthesis and antitumor activity of novel 6,7,8-trimethoxy N-aryl-substituted-4-aminoquinazoline derivatives.

A series of 6,7,8-trimethoxy N-aryl-substituted-4-aminoquinazoline derivatives were synthesized as epidermal growth factor receptor (EGFR) inhibitors, and their antitumor activities were assessed in the gastric cancer cell line SGC7901 using MTT assay. All compounds of Tg1-14 were found to inhibit SGC7901 cell proliferation, and compound Tg11 (IC50 = 0.434 µM) was found to be slightly more effective against SGC7901 cells than epirubicin (IC50 = 5.16 µM). This suggests that compound Tg11 can be used as a new substitution structure to develop more efficacious antitumor agents. Western blot analysis showed that treatment with Tg11 (40 µM for 30 min) resulted in near complete inhibition of EGF-induced ERK1/2 phosphorylation, indicating that its anti-proliferative effect is largely associated with inhibition of ERK1/2 activation. These data imply that Tg11 is a potential anticancer agent capable of inhibiting cell proliferation.

Antimicrobial Activity of Quinazolin Derivatives of 1,2-Di(quinazolin-4-yl)diselane against Mycobacteria.

Mycobacterium tuberculosis (M. tuberculosis) is one of the leading causes of morbidity and mortality. Currently, the emergence of drug resistance has an urgent need for new drugs. In previous study, we found that 1,2-di(quinazolin-4-yl)diselane (DQYD), a quinazoline derivative, has anticancer activities against many cancers. However, whether DQYD has the activity of antimycobacterium is still little known. Here our results show that DQYD has a similar value of the minimum inhibitory concentration with clinical drugs against mycobacteria and also has the ability of bacteriostatic activity with dose-dependent and time-dependent manner. Furthermore, the activities of DQYD against M. tuberculosis are associated with intracellular ATP homeostasis. Meanwhile, mycobacterium DNA damage level was increased after DQYD treatment. But there was no correlation between survival of mycobacteria in the presence of DQYD and intercellular reactive oxygen species. This study enlightens the possible benefits of quinazoline derivatives as potential antimycobacterium compounds and furtherly suggests a new strategy to develop new methods for searching antituberculosis drugs.

4-Anilinoquinazoline Derivatives with Epidermal Growth Factor Receptor Inhibitor Activity.

4-Anilinoquinazoline derivatives possess high anti-cancer activities. Many of them are highly selective tyrosine kinase inhibitors (TKI), particularly against epidermal growth factor receptor (EGFR). EGFRs are overexpressed or mutated in most carcinomas and are required for tumor progression. The efficacy of EGFR-targeted anti-tumor drugs is impaired by drug-induced acquired resistance. Therefore, there is urgency to find better anti-cancer agents with novel effects on EGFR. 4-Anilinoquinazolines are small molecule EGFR inhibitors that have been synthesized and assessed for their anti-tumor bioactivity. In this paper, we review the 4-anilinoquinazoline derivatives with EGFR inhibitor activity reported in recent years.

Preliminary evaluation of the in vitro efficacy of 1, 2-di (quinazolin-4-yl) diselane against SiHa cervical cancer cells.

Cervical cancer is one the most common malignancies among females. In recent years, its incidence rate has shown a rising trend in some countries so that development of anticancer drugs for cervical cancer is an urgent priority. In our recent anticancer drug discovery screen, 1, 2-di (quinazolin-4-yl)diselane (LG003) was found to possess wide spectrum anticancer efficacy. In the present work, the in vitro anticancer activity of LG003 was evaluated in the SiHa cervical cancer cell line. Compared with commercial anticancer drugs 10-hydroxycamptothecin, epirubicin hydrochloride, taxol and oxaliplatin, LG003 showed better anticancer activity. Furthermore, inhibition effects were time- and dose-dependent. Morphological observation exhibited LG003 treatment results in apoptosis like shrinking and blebbing, and cell membrane damage. Lactate dehydrogenase release assay revealed that LG003 exerts such effects in SiHa cells through a physiology pathway rather than cytotoxicity, which suggests that title compound LG003 can be a potential candidate agent for cervical cancer.

Synthesis and anticancer activities of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline derivatives.

A series of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline was prepared by conventional heating methods. Among these compounds, the crystal structure of compound 10o (CCDC: 916922) was determined by X-ray crystallography. Bioassay results showed that most target compounds had certain inhibition activities against proliferation of tumor cells, and some compounds even had good broad-spectrum inhibition activities. The ethoxyl series of compounds possessed higher inhibition activities against tumor cells than the methoxyl series of compounds. Bioactivity tests showed that the IC50 values of compound 10s against PC3, MGC803, A375, and A549 cells were 1.8, 2.8, 1.3, and 2.9 µΜ, respectively, which were much higher than those of commercial gefitinib (7.2, 7.6, 7.2, and 9.8 µM, respectively). Conversely, the IC50 values of compound 10s were very low against NH3T3, indicating only weak effect on normal cells as also proven by lactate dehydrogenase and acridine orange/ethidium bromide staining. Analyses of cell configuration and cell cycle revealed that compound 10s possibly caused cells to remain at G0/G1 phase by inhibiting cell proliferation for 24 h. Compound 10s also inhibited the phosphorylation of ERK1/2 and P38 with obvious concentration dependence. Thus, these compounds can inhibit the proliferation of A549 cells through the interruption of ERK1/2 and P38signaling pathways.

[Antibacterial mechanism of sulforaphane on Escherichia coli].

OBJECTIVE: To investigate the antibacterial mechanism of sulforaphaneon (SFN) on Escherichia coli. METHODS: To determine membrane penetrability, changes of SDS-PAGE protein spectra, soluble protein and alkaline phosphatase and reducing sugar were determined. Cellular nucleic acid synthesis was detected by 4, 6- diamidino-2-phenylindole (DAPI) staining assay. RESULTS: SFN affected the membrane permeability of Escherichia coli. Ions and small molecules could leak out of the cells. But it did not destroy the membrane integrity directly. After 16 hours of treatment with SFN, the total contents of intracellular and extracellular proteins decreased by 42.5% and 17.6%, respectively, while the quantity of DNA and RNA reduced by 34.8% and 48.5% respectively. CONCLUSION: SFN can affect cell membrane permeability, material and energy metabolism and inhibit the synthesis of nucleic acid and protein.

Anti-tumour activity of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline against tumour cells in vitro.

In order to create novel, potent and selective anti-cancer agents, the action of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline (compound 1018) on 10 different kinds of tumour cells were assayed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide]. It possesses a broad spectrum of anti-cancer activity. The mechanism of action of 4-(4-fluorophenyl)amino-5,6,7-trimethoxyquinazoline (hereafter referred to as compound 1018) against tumour cells was studied in androgen-independent prostate cancer PC-3 cells by microscopic observation, LDH (lactate dehydrogenase) release assay and Western blotting. Its activity was dose-dependent, with an IC50 of 13.0±1.4 µM after 72 h treatment. Microscopy and LDH release assay indicated that the effect was through anti-proliferation rather than cytotoxicity. Western blot analysis also showed that treatment of cells with 50 µM compound 1018 for 30 min almost completely inhibited EGF (epidermal growth factor)-induced phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2), which suggests that its anti-proliferative effect is largely associated due to ERK1/2 activation being inhibited. Thus compound 1018 is a potential anti-cancer agent.