Angoline: A selective IL-6/STAT3 signaling pathway inhibitor isolated from Zanthoxylum nitidum

STAT3 signaling pathway is an important target for human cancer therapy. Thus, the identification of small-molecules that target STAT3 signaling will be of great interests in the development of anticancer agents. The aim of this study was to identify novel inhibitors of STAT3 pathway from the roots of Zanthoxylum nitidum (Roxb.) DC. The bioassay-guided fractionation of MeOH extract of Z. nitidum using a STAT3-responsive gene reporter assay led to the isolation of angoline (1) as a potent and selective inhibitor of the STAT3 signaling pathway (IC₅₀ = 11.56 μM). Angoline inhibited STAT3 phosphorylation and its target gene expression and consequently induced growth inhibition of human cancer cells with constitutively activated STAT3 (IC₅₀ = 3.14–4.72 μM). This work provided a novel lead for the development of anti-cancer agents targeting the STAT3 signaling pathway.     

Design,synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors

STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC₅₀ values as low as 7.71 μM and 1.38 μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC₅₀ value of 9.61 μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.     

Synthesis and biological evaluation of novel isothiazoloquinoline quinone analogues

Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC₅₀ values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further exploration of possible mechanism of action indicates that 13a not only activates ROS production through NQO1-directed redox cycling but also inhibits the phosphorylation of STAT3. These findings indicate that 13a has potential use for the development of new skeleton drug candidate as an efficient substrate of NQO1 and STAT3 inhibitor.     

Synthetic derivatives of the natural product 13-amino 2-desoxy-4-epi-pulchellin inhibit STAT3 signaling and induce G2/M arrest and death of colon cancer cells

2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs.     

Antitumor agents 270. Novel substituted 6-phenyl-4H-furo[3,2-c]pyran-4-one derivatives as potent and highly selective anti-breast cancer agents

6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10–13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100–250-fold more potent against SK-BR-3 (ED₅₀ 0.28 and 0.44 μM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents.     

Synthesis and biological evaluation of benzo[b]furo[3,4-e][1,4]diazepin-1-one derivatives as anti-cancer agents

A new series of novel Podophyllotoxin-like benzo[b]furo[3,4-e][1,4]diazepin-1-ones possessing structural elements of 4-aza-2,3-didehydropodophyllotoxins with central diazepine ring was designed and synthesized as anti-cancer agents. In initial assessment, the cytotoxic activity of the synthesized compounds was evaluated against three cancer cell lines including MCF-7, PC3 and B16-F10 employing the MTT assay. Some of compounds (12h, 13a, 13c and 14b) showed significant cytotoxic activity. So, we investigated the cytotoxicity of compounds 12h, 13a, 13c and 14b, along with podophyllotoxin as the reference drug in different cancer cell lines including A549, A2780, DU145, HeLa, and normal Huvec cell line. Among these four compounds, 13c showed promising antiproliferative activity against all cancer cells stronger than the other compounds and comparable to reference drug podophyllotoxin in some cancer cells. All these four compounds did not show significant cytotoxicity on normal Huvec cell line. The flow cytometry analysis of the MCF-7, PC3 and A2780 human cancer cell lines treated with 13c showed that 13c, induced apoptosis in the MCF-7, PC3 and A2780 human cancer cell lines, which is in good agreement to its cytotoxic activity as well. Compound 13c did not show significant influence on tubulin assembly and exert its cytotoxic effects via induction of apoptosis and has potent and selective cytotoxic effects in cancer cells.     

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.     

Synthesis and biological evaluation of novel isoxazoles and triazoles linked 6-hydroxycoumarin as potent cytotoxic agents

A new series of diverse isoxazoles and triazoles linked 6-hydroxycoumarin (1) were synthesized using click chemistry approach. All the derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) cytotoxicity screening against a panel of five different human cancer cell lines viz. prostate (PC-3), colon (HCT-116 and Colo-205), leukemia (HL-60) and lung (A-549) to check their cytotoxic potential. Interestingly, among the tested molecules, some of the analogs displayed better cytotoxic activity than the parent 6-hydroxycoumarin (1). Of the synthesized isoxazoles, compounds 10 and 13 showed the best activity with IC₅₀ of 8.2 and 13.6 μM against PC-3 cancer cell line, while as, among the triazoles, compounds 23 and 25 were the most active with the IC₅₀ of 10.2 and 12.6 μM against A-549 cancer cell line. The other derivatives showed almost comparable activity with that of the parent molecule. The present study resulted in identification of ortho substituted isoxazole and triazole derivatives of 6-hydroxycoumarin as effective cytotoxic agents against prostate (PC-3) and lung (A-549) cancer cell lines, respectively.     

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.     

Pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones protect SHSY-5Y cells from Cd-induced apoptosis involving suppression of endoplasmic reticulum stress

Cadmium (Cd) is a potent toxic heavy metal, some studies showed that Cd-induced apoptosis is through ER stress pathway. Compounds of pyrrolo[2,1–c][1,4]benzodiazepine (PBD)-3,11-diones were discovered as potent neuroprotective agents against Cd-induced toxicity in SH-SY5Y cells for the first time. In this study, twenty-six PBD-3,11-dione derivatives were synthesized and evaluated for their neuroprotective activity against Cd-induced toxicity by CCK-8 assay. Their preliminary SARs studies indicated that various substituents were tolerated on the benzene ring, and alkyl heterocycles groups at the N10-position of the PBD-3,11-dione scaffold were important for the activities. Among them, compound 13c exhibited the best activity (cell viability?=?68.6%, 25?μM). Furthermore, we found that the compound 13c could inhibit cadmium-induced cell apoptosis with the downregulation of the ER stress markers GRP78, CHOP, cleaved-caspase12 and cleaved-caspase3 through western blotting. The results of in silico evaluation of ADME/T properties showed that 13c exhibited medium BBB penetration level and promising toxicity profiles. These results proved the potential of 13c as a promising lead compound against Cd-induced neurotoxicity.     

Design and synthesis of 21-alkynylaryl pregnenolone derivatives and evaluation of their anticancer activity

A series of novel C21-alkynylaryl derivatives of pregnenolone were synthesized and screened for anticancer activity against a panel of seven human cancer cell lines (LNCaP, A549, MCF7, HeLa, A431, HepG2, HT29). The data revealed that these compounds can be potential antitumour agents against the specific cell models. Compound 6f bearing a 2-trifluoromethylphenyl group displayed improved cytotoxicity towards all cancer cell lines used. A431 cells were the most sensitive with derivatives 6e–6h bearing electron withdrawing substituents exhibiting high potency with IC₅₀ values ranging between 2.18 and 0.54 μM and drastic inhibition of the prosurvival PI3K-Akt/PKB pathway.     

Synthesis and biological evaluation of 2′,5′-dimethoxychalcone derivatives as microtubule-targeted anticancer agents

A series of novel 2′,5′-dimethoxylchalcone derivatives including 18 new compounds were synthesized and evaluated for cytotoxicities against two human cancer cell lines, NTUB1 (human bladder cancer cell line) and PC3 (human prostate cancer cell line). All these derivatives except for 21 exhibited significant cytotoxic effect against NTUB1 and PC3 cell lines. Compounds 13 and 17 with 4-carbamoyl moiety showed potent inhibitory effect on growth of NTUB1 and PC3 cells. Flow cytometric analysis demonstrated that treatment of NTUB1 cells with 1 μM 13 and 17 induced G1 phase arrest accompanied by an increase in apoptotic cell death of NTUB1 cells after 24 h. Treatment of PC3 cells with 1 μM and 3 μM 13, and 1 μM and 3 μM 17 induced S and G1, and G1 and G2/M phase arrests, respectively, accompanied by an increase in apoptotic cell death. These data suggested that 13 and 17 with different 4-carbamoyl moiety displayed same cell cycle arrest in NTUB1 cells while different doses of 13 and 17 revealed different cell cycle arrest in PC3 cells. Cell morphological study of 17 indicated that more cells rounding up or dead associated with tubulin polymerization. Compound 17 showed an increased α-tubulin level in polymerized microtubule fraction in a dose-dependent manner while 500 nM paclitaxel also showed similar effect in NTUB1 cells by Western blot analysis. The result suggested that 17 may be used as microtubule-targeted agents.