Synthesis of novel deuterated EGFR/ALK dual-target inhibitors and their activity against non-small cell lung cancer.

EGFR and ALK are common driver genes in NSCLC, and more patients with these mutations are being identified due to medical advances. Thus, developing dual-target EGFR/ALK inhibitors is crucial. In this study, 10 novel small molecules were designed and synthesized.

Inhibition of TGF-β1/Smad3 signaling by compound 5aa: A potential treatment for idiopathic pulmonary fibrosis.

The incidence of idiopathic pulmonary fibrosis (IPF) has been steadily increasing each year, posing significant challenges in its treatment. In this study, we conducted the design and synthesis of 23 new inhibitors that specifically target the TGF-β1/Smad3 pathway. Initially, we employed a cell model of TGF-β-induced pulmonary fibrosis, using cell survival rate and HYP expression as indicators to identify the potent ingredient 5aa, which demonstrated significant anti-pulmonary fibrosis activity.

The new N, N-diphenylpyridine-2,4-diamine deuterated derivatives as EGFR inhibitors to overcome C797S-mediated resistance.

A series of new deuterated and non-deuterated N, N-diphenylpyridine - 2,4-diamine derivatives were synthesized and evaluated as EGFR C797S-mediated resistance inhibitors. Most of these compounds exhibited potent antiproliferative activity against Baf3-EGFR and Baf3-EGFR cancel cell lines, with IC values in the nanomolar concentration range. Among them, compound 14l represented the most active compound with IC values of 8-11 nM.

Glucagon Enhances Chemotherapy Efficacy By Inhibition of Tumor Vessels in Colorectal Cancer.

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy.

A novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation.

Multiple tumors are synergistically promoted by c-Met and TRK, and blocking their cross-signalling pathway may give better effects. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited excellent anti-tumor activity by targeting c-Met and TRK. Models in vitro, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the positive drug Tepotinib.

Discovery of potent and effective inhibitors containing sulfoxide structures targeting EML4-ALK rearrangement and EGFR mutant non-small cell lung cancer.

For non-small cell lung cancer patients with dual mutations in EGFR and ALK, there are currently no effective therapies. Consequently, novel EGFR/ALK dual-target inhibitors are urgently needed for the treatment of NSCLC. Here, we designed a series of highly effective small molecule dual inhibitors of ALK and EGFR.

Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer.

ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors.

Discovery of a potent EGFR and ALK dual mutation inhibitor containing N-(3-((4-((2-(cyclopropylsulfinyl)phenyl)amino)pyrimidin-2-yl)amino) phenyl)acrylamide scaffold.

A series of EGFR and ALK dual inhibitors containing sulfoxide and cyclopropyl groups were designed and synthesized. The lead compound 8a showed a significant activity against EGFR and ALK in both the enzymatic and cellular assays. The study of anti-tumor mechanism indicated that 8a could effectively block the phosphorylation of EGFR and ALK proteins, so as to effectively inhibiting the proliferation and inducing apoptosis of H1975 tumor cells, blocking the cell cycle and reducing the mitochondrial membrane potential inhibited the migration of H1975 cells.

Synthesis and evaluation of new pirfenidone derivatives as anti-fibrosis agents.

Two series of new pirfenidone derivatives, in which phenyl groups or benzyl groups are attached to the nitrogen atom of the pyridin-2(1)-one moiety were synthesized and evaluated as anti-fibrosis agents. Among them, compound 5d, with a ()-2-(dimethylamino) propanamido group in the R position (series 1) exhibited 10 times the anti-fibrosis activity (IC: 0.245 mM) of pirfenidone (IC: 2.

A Multifunctional Vanadium-Iron-Oxide Nanoparticle Eradicates Hepatocellular Carcinoma via Targeting Tumor and Endothelial Cells.

Nanoparticles are widely used in biological research and cancer therapy. In hepatocellular carcinoma, several nanoplatforms have been synthesized and studied to improve the drug efficacy; however, these nanoplatforms are still insufficient to eradicate tumors. Herein, we have synthesized a novel vanadium (V)-iron-oxide (ION) nanoparticle (VIO) that combines chemodynamic, photothermal, and diagnostic capacities to enhance the tumor suppression effect in one agent with multiple functions.

Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer.

The critical T790M secondary mutation in epidermal growth-factor receptor (EGFR) mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Herein, we identified 12 new 2,4-diaryl pyrimidine derivatives containing thiophene fragments as new selective third-generation EGFR inhibitors. Among them, Compound 6a showed good inhibitory activity against EGFR mutant cells with an IC value of 0.

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents.

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib.

Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors.

The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer.

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC values of 4.10 nM and 10 nM, respectively.

Design, synthesis, and biological evaluation of novel benzodiazepine derivatives as anticancer agents through inhibition of tubulin polymerization in vitro and in vivo.

A series of novel structurally-related tubulin polymerization inhibitors based on benzodiazepine were designed, synthesized, and evaluated for anticancer activity. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Most compounds exhibited potent antiproliferative activity against a panel of cancer cell lines.

Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents.

Inspired by the potent inhibition activity of the c-Met (mesenchymal-epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound exhibited potent antiproliferative activity (IC (50% inhibitory concentration) = 0.026 μΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells.

Synthesis and evaluation of clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of Alzheimer's disease.

Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of AD. In vitro studies demonstrated that some of the molecules processed remarkable inhibitory activity against phosphodiesterase 4D (PDE4D), strong intracellular antioxidant capacity, potent inhibition of metal-induced aggregation of Aβ, and potential blood-brain barrier permeability. Compound 7a demonstrated significant improvement in cognitive and spatial memory in an Aβ-induce mouse model in Morris water-maze test (MWM).

Design, synthesis, and biological evaluation of histone deacetylase inhibitors possessing glutathione peroxidase-like and antioxidant activities against Alzheimer's disease.

A series of hybrids containing the pharmacophores of the histone deacetylase (HDAC) inhibitor, SAHA, and the antioxidant ebselen were designed and synthesized as multi-target-directed ligands against Alzheimer's disease. An in vitro assay indicated that some of these molecules exhibit potent HDAC inhibitory activity and ebselen-related pharmacological effects. Specifically, the optimal compound 7f was found to be a potent HDAC inhibitor (IC = 0.

Evaluation of 4-phenylamino-substituted naphthalene-1,2-diones as tubulin polymerization inhibitors.

A series of 4-phenylamino-substituted naphthalene-1,2-dione derivatives were prepared and evaluated as effective antiproliferative agents. MTT assays showed that the compounds with a methyl group on the nitrogen linker exhibited potent antiproliferative activities against human cancer cells. The mechanistic study revealed that these compounds could induce mitochondrial depolarization, which resulted in intracellular ROS production, and they also acted as tubulin polymerization inhibitors.

The design, synthesis and evaluation of selenium-containing 4-anilinoquinazoline hybrids as anticancer agents and a study of their mechanism.

Inhibition of tubulin polymerization is one of the significant strategies in the treatment of cancer. Inspired by the excellent antitumor activity of EP128495 and the beneficial biological activities of selenium compounds, a series of new selenium-containing 4-anilinoquinazoline hybrids were synthesized and evaluated as tubulin polymerization inhibitors. An anti-proliferative activity assay showed that most of the compounds inhibited human sensitive cancer cells at low nanomolar concentrations.

Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization inhibitors.

Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization.

Synthesis and Biological Evaluation of Selenium-Containing 4-Anilinoquinazoline Derivatives as Novel Antimitotic Agents.

Twenty-eight novel selenium-containing 4-anilinoquinazoline derivatives were designed, synthesized, and evaluated as antiproliferative agents. Most of them had significant in vitro activities, particularly for compounds 23a, 25a, and 25d, which also exhibited the most potent antitumor activities against cisplatin-resistant cell lines and the doxorubicin-resistant cell lines, good selectivity toward normal cells, and obvious inhibitory effect on migration of A549 cell lines. Further mechanistic studies revealed that 23a, 25a, and 25d induce G2/M phase arrest and apoptosis in A549 cells, which was associated with a collapse of the mitochondrial membrane potential, alterations in the expression of some cell cycle-related and apoptosis-related proteins, and increasing the intracellular ROS level.

Synthesis and evaluation of selenium-containing indole chalcone and diarylketone derivatives as tubulin polymerization inhibition agents.

Sixteen new selenium-containing indole chalcone and diarylketone derivatives were synthesized and evaluated as tubulin polymerization inhibitors. Among them, compound 25b exhibited the most potent antiproliferative activities against six human cancer cell lines with IC values of 0.004-0.

Design, Synthesis, and Biological Evaluation of Novel Selenium-Containing Isocombretastatins and Phenstatins as Antitumor Agents.

Two series of structurally related organoselenium compounds designed by fusing the anticancer agent methyl(phenyl)selane into the tubulin polymerization inhibitors isocombretastatins or phenstatins were synthesized and evaluated for antiproliferative activity. Most of these selenium containing hybrids exhibited potent cytotoxicity against a panel of cancel cell lines, with IC values in the submicromolar concentration range. Among them, 11a, the 3-methylseleno derivative of isocombretastatin A-4 (isoCA-4) represented the most active compound with IC values of 2-34 nM against 12 cancer cell lines, including two drug-resistant cell lines.

The synthesis and evaluation of new butadiene derivatives as tubulin polymerization inhibitors.

A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC values of 0.056-0.