Search

Starting with our previously reported work, a novel series of 3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-derivatives were designed, synthesized and evaluated as potent EGFR tyrosine kinase inhibitors. All of the compounds showed significant inhibitory activities against EGFR wt kinase (IC 50  ≤ 937.7 nM). Among them, compound 7j demonstrated the most potent inhibitory activity toward EGFR wt tyrosine kinase with IC 50 value of 25.69 nM and showed good antiproliferative activities against NCI-H1563 and H1975 cells. The median cytotoxic concentration (CC 50 ) showed that most of the tested compounds displayed almost no cytotoxicity in vitro against 16HBE cells. In view of the reported compounds activity, the structure deserves further optimization as cancer treatment agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). The first-generation EGFR tyrosine kinase inhibitors (TKIs) Gefetinib and Elotinib showed good clinical efficacy on lung adenocarcinoma tumors, but almost all patients developed resistance to these inhibitors over time. Quinazoline and quinoline derivatives are common targeted inhibitors of EGFR kinase, and their structural optimization is an important direction for the development of effective targeted anticancer drugs. Based on these facts, a series of heterocyclic 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives have been designed and synthesized and their structures were confirmed by spectral analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against the human kidney epithelial T293 cell line, normal lung cell lines WI-38, non-small cell lung cancer A549 and NCI-H157 cell lines using MTT. The tested compounds showed an evident anticancer activity against the tested cell lines, especially compound 13c, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC 50 ) between 8.82 and 10.24 μM. Docking study showed that compound 13b could be nicely bound to the ATP binding pocket of EGFR. In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC 50 ) in the range of 10.29 nM to 652.3 nM. In view of the reported compound activity, the structure deserves further optimization as cancer treatment agents., (Copyright © 2021. Published by Elsevier Inc.)

Twelve 2,3-dihydro-[1,4]-dioxino[2,3-f]quinazoline derivatives were designed and evaluated as vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. The most half-maximal inhibitory concentration (IC 50 ) values of them were less than 10 nM. Among these compounds, 13d displayed highly effective inhibitory activity against VEGFR-2 (IC 50  = 2.4 nM) and excellent antiproliferative activities against human umbilical vein endothelial cells (HUVECs) (IC 50  = 1.2 nM). When anti-tumor animal experiments were carried out in mice, the tumor almost disappeared (TGI = 133.0%) after six days of administration of 13d. Therefore, 13d was a potential and effective anticancer agent. The binding conformations were respectively compared between VEGFR-2 with 13d and leading compound lenvatinib, and shows that they have similar binding modes., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC 50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Protein kinase CK2 has emerged as an attractive cancer therapeutic target. Previous studies have highlighted the challenge of optimizing CK2 ATP-competitive inhibitors that have low druggability due to their polycyclic ring scaffolds. Therefore the development of novel inhibitors with non-polycyclic scaffolds emerges as a promising strategy for drug discovery targeting CK2. In this current study, based on the similar predicted binding poses of the linear 2-propenone scaffold of isoliquiritigenin with that of the polycyclic inhibitor CX-4945, a series of 2-propenone derivatives containing an amine-substituted five-membered heterocycle and a benzoic acid were designed, synthesized and evaluated for their in vitro CK2 inhibition and anti-cancer activity. Compound 8b was found to be the most potent CK2 inhibitor (IC 50  = 0.6 μM) with the anti-proliferative activity on HepG2 cancer cells (IC 50  = 14 μM), compared to the activity of isoliquiritigenin (IC 50  = 17 μM and 51 μM, respectively). Molecular docking was performed to understand the binding modes of the newly designed 2-propenone derivatives with CK2. Compound 8b formed the most favorable network of hydrogen bonds with both the hinge region and positive area. Our results indicate that CK2 derivatives with a linear 2-propenone scaffold are promising candidates for anti-cancer drug discovery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inspired by the significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP, 1), we synthesized and characterized a series of novel 5α,8α-epidioxyandrost-3β-ol-17-(O-phenylacetamide)oxime derivatives (9a-o). The anti-proliferative activity of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, Sk-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. Compounds 9d, 9f, 9h, 9j and 9m displayed good anti-proliferative activity (most IC 50 <20μM) in vitro. Furthermore, fluorescence imaging showed that the designed coumarin-9d conjugate (12) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

By inspiration of significant anti-cancer activity of our previously screened natural ergosterol peroxide (EP), a series of novel steroidal 5α,8α-endoperoxide derivatives 5a-d and 14a-f were designed, synthesized, and biologically evaluated for their in vitro anti-proliferative inhibitory and cytotoxic activity. The results revealed that most of these compounds showed moderate-to-excellent anti-proliferative effects against the tested cancer cell lines (i.e. HepG2, SK-Hep1, MDA-MB-231 and MCF-7). Among them, compound 5b and 14d exhibited preferable inhibitory activities (IC 50 of 5b and 14d are 8.07 and 9.50μM against HepG2, respectively). The structure-activity relationships indicated that incorporation the peroxidic bridge to the steroid scaffolds at C-5 and C-8 positions together with the aliphatic side-chain at the C-17 position would provide synergistic effect for the bioactivity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inspired by the significant anticancer activity of our previously screened natural ergosterol peroxide (1), we synthesized and characterized a series of novel ergosterol peroxide 3-carbamate derivatives. The antiproliferative activities of the synthesized compounds against human hepatocellular carcinoma cells (HepG2, SK-Hep1) and human breast cancer cells (MCF-7, MDA-MB231) were investigated. 5α,8α-Epidioxyergosta-3-yl-(piperazine-1)carbamate (3 d) and 5α,8α-epidioxyergosta-3-yl-(piperidin-4-methylamine)carbamate (3 f) and their hydrochloride salts exhibited significant in vitro antiproliferative activities against the tested tumor cell lines, with IC 50 values ranging from 0.85 to 4.62 μm. Furthermore, fluorescent imaging showed that the designed coumarin-3 d conjugate (5) localized mainly in mitochondria, leading to enhanced anticancer activities over the parent structure 1. As a whole, it appeared that substituent changes at the C3 position could serve as a promising launch point for further design of this type of steroidal anticancer agent., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFR(wt) kinase (IC50<1 μM). Compound a8 demonstrated the most potent inhibitory activity toward EGFR(wt) (IC50=53.1 nM). Compound a7 and a8 showed excellent inhibitory activities against mutant EGFR(T790M/L858R) and strong antiproliferative activity against H358 and A549 cell lines. Finally, molecular docking studies were performed to predict the possible binding mode of the target compounds. It is believed that this work would be very useful for designing a new series of tyrosine kinase inhibitors targeting EGFR., (Copyright © 2016. Published by Elsevier Ltd.)

4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR-ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR-ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR-ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR-ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR-ABL kinase structure active site to determine the probable binding model. The preliminary structure-activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

With the successful use of gefitinib and erlotinib in clinic, some potent EGFR tyrosine kinase receptor inhibitors have gained widespread concern in the treatment of ovarian or non-small-cell lung cancer. However, the emergence of EGFR-activating mutations resist to the drugs, there is an impending need to design new inhibitor targeted EGFR. Furthermore, the understanding of mutual effect between EGFR and drug has been available, it has become a hot spot for the research of anticancer drugs. We have designed and synthesized a series of 6-methoxy-7-(3-morpholinopropoxy)-1-(2- phenoxyethyl)-quinoxalin-2(1H)-one derivatives as novel EGFR inhibitors. Most of the compounds have showed inhibitory activity toward EGFR kinase. This work has demonstrated it is possible to construct a new type of EGFR protein kinase inhibitor using a designin strategy.

Rosavin was a major active compound from Rhodiola rosea. It is known that it possesses stimulant, antidepressant, and anticancer properties. In the present study, a two-step flash column chromatography has been developed for the large-scale preparative separation and purification of rosavin from the extracts of Rhodiola rosea, which were obtained by microwave assisted extraction (MAE) using ion liquids (ILs) as extraction solvent under the optimized conditions (microwave power 1200 W, extraction time 6 min, solid-liquid ratio 1:20, microwave temperature 120°C) resulting from the analysis of the D-optimal design. In the first separation, the Rhodiola rosea extract was loaded into polyamide and HPD-200 macroporous resin flash columns in series for efficient enrichment of rosavin. In the second one, the rosavin-rich crude sample after the serial column chromatography was subjected to final purification by silica gel flash chromatography. After the two-step separation, 529.1 mg of rosavin was obtained at a purity of 98.2% and a recovery of 60.6%. The separation process can provide a new method for large-scale separation and purification of rosavin for its pharmaceutical and practical use. [ABSTRACT FROM PUBLISHER]

A novel poly( l-aspartic) derivative (PAL-DPPE) containing polylactide and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) segments has been successfully synthesized. The chemical structures of the copolymers were confirmed by Fourier-transform infrared spectroscopy (FTIR), NMR (H NMR, C NMR, P NMR), and thermogravimetric analysis (TGA). Fluorescence spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM) confirmed the formation of micelles of the PAL-DPPE copolymers. In order to estimate the feasibility as novel drug carriers, an anti-tumor model drug doxorubicin (DOX) was incorporated into polymeric micelles by double emulsion and nanoprecipitation method. The DOX-loaded micelle size, size distribution, and encapsulation efficiency (EE) were influenced by the feed weight ratio of the copolymer to DOX. In addition, in vitro release experiments of the DOX-loaded PAL-DPPE micelles exhibited that faster release in pH 5.0 than their release in pH 7.4 buffer. The poly( l-aspartic) derivative copolymer was proved to be an available carrier for the preparation of micelles for anti-tumor drug delivery. [ABSTRACT FROM AUTHOR]