Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor

A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC₅₀ = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-β and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R² = F) on R, R¹ and R², respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.     

Discovery of novel 4(1H)-quinolone derivatives as potential antiproliferative and apoptosis inducing agents

A series of novel 4(1H)-quinolone derivatives was synthesized and evaluated for antiproliferative activity in vitro. The results showed that these compounds exhibited more potent antiproliferative effect against a panel of human tumor cell lines than the lead compound 7-chloro-4(1H)-quinolone 1. Compound 7e was found to be the most potent antiproliferative agent and to exhibit selective cytotoxic activity against HepG2 cell lines with IC₅₀ value lower than 1.0 μM. Annexin V/FITC-PI assay showed that compound 7e induced apoptosis in HepG2 cells with a dose-dependent manner. Western blotting analysis indicated that compound 7e induced cell cycle arrest in G2/M phase by p53-depedent pathway.     

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.     

Design,synthesis and biological activities of sorafenib derivatives as antitumor agents

A series of novel sorafenib derivatives, 9a–w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC₅₀ = 2.8–52.0 and 2.2–45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents

In this research, a series of 4-(1,2,3-triazol-1-yl)coumarin conjugates were synthesized and their anticancer activities were evaluated in vitro against three human cancer cell lines, including human breast carcinoma MCF-7 cell, colon carcinoma SW480 cell and lung carcinoma A549 cell. To increase the biological potency, structural optimization campaign was conducted focusing on the C-4 position of 1,2,3-triazole and the C-6, C-7 positions of coumarin. In addition, to further evaluate the role of 1,2,3-triazole and coumarin for antiproliferative activity, 9 compounds possessing 4-(piperazin-1-yl)coumarin framework and 3 derivatives baring quinoline core were also synthesized. By MTT assay in vitro, most of the compounds display attractive antitumor activities, especially 23. Further flow cytometry assays demonstrate that compound 23 exerts the antiproliferative role through arresting G₂/M cell-cycle and inducing apoptosis.     

Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors

A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC₅₀ value of 1.04 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.     

Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents

Acridine derivatives have been explored as DNA-binding anticancer agents. Some derivatives show undesired pharmacokinetic properties and new derivatives need to be explored. In this work, a series of novel acridine analogues were synthesized by modifying previously unexplored linkers between the acridine and benzene groups and their antiproliferative activity and the DNA-binding ability were evaluated. Among these derivatives, compound 5c demonstrated DNA-binding capability and topoisomerase I inhibitory activity. In K562 cell lines, 5c induced apoptosis through mitochondria-dependent intrinsic pathways. These data suggested that compound 5c and other acridine derivatives with modified linkers between the acridine and benzene groups might be potent DNA-binding agents.     

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors

A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure–activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC₅₀ value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.     

Discovery of novel 1,5-benzodiazepine-2,4-dione derivatives as potential anticancer agents

A series of novel 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents were designed and synthesized using three-component reactions. The preliminary assays showed that most of them displayed moderate to good antitumor activities against human lung carcinoma (A549), human breast epithelial carcinoma (MCF-7), human colon carcinoma (HCT116), human cervical carcinoma (Hela) and Lewis lung carcinoma (2LL). Exhilaratingly, the activity level of 6m rivaled that of 5-Fluorouracil (5-Fu) against MCF-7 cell lines, which might be used as novel lead scaffold for potential anticancer development.     

Design,synthesis and biological evaluation of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC₅₀ = 1.63 nM) was identified, which showed the most potent antitumor activities with IC₅₀ values of 0.055 μM, 0.071 μM, 0.13 μM, and 0.43 μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.     

Design,synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC₅₀ value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC₅₀ values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.     

Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents

A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC₅₀?=?3.73?nM) and is a promising candidate for further development in therapeutics for cancer.     

Design,synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents

Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MTT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC₅₀ = 16.57, 5.45, 4.42 and 5.16 μM) and 33e (IC₅₀ = 20.14, 6.71, 4.62 and 5.62 μM) showed excellent anti-proliferative activities on MCF-7, HepG2, HCT116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties.     

Novel carbazole sulfonamide derivatives of antitumor agent: Synthesis,antiproliferative activity and aqueous solubility

The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a–13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC₅₀ values against the four cell lines comparable to those for 3. Two compounds (13f and 13i) were more active than 3 and their activity against HepG2 and MCF-7 (IC₅₀:0.01–0.07 μM) approached that of the positive controls podophyllotoxin (podo) and CA-4. Most of compounds showed aqueous solubility (0.11–19.60 μg/mL at pH 7.4 and 2.0) better than 3. These promising results warrant further development of new compounds 13f and 13i as potential potent antitumor drug candidates.     

Discovery of novel pyrazole derivatives as potential anticancer agents in MCL

Mantle cell lymphoma (MCL) is characterized by the translocation t(11;14) (q13;q32), resulting in the overexpression of cyclin-D1. The progression of MCL is an interaction of multitarget and multilink regulation. It has been proven that Bruton’s tyrosine kinase (BTK) is commonly overexpressed in MCL, which makes it a focus of targeted therapy for MCL. Irreversible inhibitors usually have great potency, rapid onset of inhibition and long duration of drug action. Herein, structural modification via an open-loop strategy based on lead compound ibrutinib (IBN) was performed, leading to a series of pyrazole derivatives. Compounds 19c, 19′c, 21c and 21′c showed potent effect in MCL cells with IC₅₀ values lower than 1?μM, and a more than 3-28-fold increase in antiproliferative activity compared with IBN.     

Design,synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents

HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivatives that combine the inhibitory activities of BRD4 and HDAC into one molecule were designed and synthesized through the structure-based design method. Most compounds showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compounds were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC₅₀ value of 5 nM and BRD4 inhibition rate of 88% at 10 μM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot analysis. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.     

Discovery and synthesis of novel 3-phenylcoumarin derivatives as antidepressant agents

A series of 3-phenylcoumarins were synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Three compounds (6, 7 and 13) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (% DID). In addition, the active antidepressant compounds were subsequently studied at their most effective dose and activity of these compounds were confirmed in forced swimming test (FST) animal model, in which the compounds at a low dose of 0.5 mg/kg significantly decreased the immobility time and exhibited greater efficacy than the reference standards fluoxetine and imipramine. The potent compounds did not show any neurotoxicity in the rotarod test and the preliminary results are promising enough to warrant further studies around this scaffold.     

Discovery of novel andrographolide derivatives as cytotoxic agents

The natural diterpenoid andrographolide (1) exhibits various biological activities. Seventeen derivatives of 1 were prepared via esterification and etherification of 14-dehydroxy-11,12-didehydroandrographolide (2). Most derivatives demonstrated significant inhibition against tumor cell growth. The most active compounds, 3b and 3c, had GI₅₀ values of 1.46–9.19 μM against A549, DU145, KB and KB-Vin tumor cells. In an immunocytochemical study, treatment with compound 3c disrupted microtubule dynamics in PC-3 cells, but caused no accumulation of metaphase cells, which is a phenotype dissimilar from that of 1. This difference suggests that structural modification of 1 resulted in a shift in the underlying molecular mechanism.     

Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h, 12b and 12d. Based on the further enzyme assay in vitro, compound 12d was considered as the most promising one, the IC₅₀ values of which were 0.11 μM and 0.19 μM for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study.     

Synthesis and evaluation of novel alkannin and shikonin oxime derivatives as potent antitumor agents

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.