[Show abstract][Hide abstract]ABSTRACT: This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11–23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 μM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 μM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.
[Show abstract][Hide abstract]ABSTRACT: Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway, and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N'-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.
No preview · Article · Dec 2015 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: We have designed and synthesized certain novel oxime- and amide-bearing coumarin derivatives as nuclear factor erythroid 2 p45-related factor 2 (Nrf2) activators. The potency of these compounds was measured by antioxidant responsive element (ARE)-driven luciferase activity, level of Nrf2-related cytoprotective genes and proteins, and antioxidant activity. Among them, (Z)-3-(2-(hydroxyimino)-2-phenylethoxy)-2H-chromen-2-one (17a) was the most active, and more potent than the positive t-BHQ in the induction of ARE-driven luciferase activity. Exposure of HSC-3 cells to various concentrations of 17a strongly increased Nrf2 nuclear translocation and the expression level of Nrf2-mediated cytoprotective proteins in a concentration-dependent manner. HSC-3 cells pretreated with 17a significantly reduced t-BOOH-induced oxidative stress. In the animal experiment, Nrf2-mediated cytoprotective proteins, such as aldo-keto reductase 1 subunit C-1 (AKR1C1), glutathione reductase (GR), and heme oxygenase (HO-1), were obviously elevated in the liver of 17a-treated mice than that of control. These results suggested that novel oxime-bearing coumarin 17a is able to activate Nrf2/ARE pathway in vivo and are therefore seen as a promising candidate for further investigation.
Full-text · Article · Oct 2015 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally-occurring substance, was found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The observable detoxifying/antioxidant genes activation by t-CA, especially heme oxygenase-1 (HO-1), was found to be involved in the cytoprotective effects against carcinogen tert-butylhydroperoxide- and arecoline-elicited oxidative stress and cell injuries. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in the ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2 -mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via the novel p38α/MAPKAPK-2- and PK-N3-dependent signaling. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential in the management of carcinogenesis, and merits for further investigation.
Full-text · Article · Aug 2015 · Chemical Research in Toxicology
[Show abstract][Hide abstract]ABSTRACT: Described herein is the development of a novel series of 7-anilino-indoline-N-benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer activity on comparing with compound 1. 7-(4-Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold better activity against KB, HT29, and MKN45 cancer cell lines with IC50 values of 49.7, 149, and 92nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a concentration-dependent manner without affecting cell viability.
No preview · Article · Jun 2014 · Bioorganic & Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 uM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1, 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, Zolinza, N-hydroxy-N'-phenyl-octanediamide) and is therefore seen as a suitable candidate for further investigation.
No preview · Article · Apr 2014 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: 2-Hydroxy-3,4,5-trimethoxybenzophenones (8-16) manifest pseudo-ring formation involving intramolecular hydrogen bonding of the 2-OH and the carbonyl group. Among the synthetic products described in this report, (3-hydroxy-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxyphenyl)-methanone (14) and (3-amino-4-methoxyphenyl)(2-hydroxy-3,4,5-trimethoxy-phenyl)methanone (16) exhibit significant antiproliferative activity against KB cells with IC 50 values of 11.1 and 11.3 nM, respectively. These two compounds also displayed tubulin affinity comparable to that of combretastatin A-4. In studies with human umbilical vein endothelial cells, compounds 14 and 16 revealed concentration-dependent vascular-disrupting properties. The results support the rationale of the pseudo-ring concept and suggest further investigation of A-ring modification in these benzophenones.
No preview · Article · Apr 2014 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: Investigation of the wood of Cunninghamia konishii resulted in the isolation and characterization of one new abietane diterpenoid, (6α,7β)-7,8-epoxy-6-hydroxyabieta-9(11),13-dien-12-one (1), and two new labdane diterpenoids, (12R)-12-hydroxylabda-8(17),13(16),14-trien-19-oic acid (2) and (12R)-12-hydroxylabda-8(17),13(16),14-trien-18-oic acid (3). The structures of these new compounds were elucidated by analysis of their spectroscopic data.
Full-text · Article · Dec 2013 · Helvetica Chimica Acta
[Show abstract][Hide abstract]ABSTRACT: Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.
No preview · Article · Oct 2013 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: Oxaliplatin treatment is a mainstay of treatment for advanced gastrointestinal tract cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain largely obscured. We previously demonstrated that increased DNA repair capacity and copper-transporting ATPase 1 (ATP7A) level contributed to oxaliplatin resistance in the human gastric carcinoma cell line TSGH-S3 (S3). In the present study, we applied gene array technology to identify additional resistance factors in S3 cells. We found that interleukin-6 (IL-6), aldo-keto reductase 1C1 (AKR1C1), and AKR1C3 are the top 3 upregulated genes in S3 cells when compared with parent TSGH cells. Despite a higher level of endogenous IL-6 in S3, IL-6 receptor (IR-6R, gp-80, and gp-130) levels were similar between TSGH and S3 cells. The addition of exogenous IL-6, IL-6 targeted siRNA, or neutralizing antibodies neither affected Stat3 activation, a downstream target of IL-6, nor changed oxaliplatin sensitivity in S3 cells. However, manipulation of AKR1C activity with siRNA or AKR1C inhibitors significantly reversed oxaliplatin resistance. AKR1Cs are classical antioxidant response element (ARE) genes that can be transcriptionally upregulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of Nrf2 not only decreased the levels of AKR1C1, AKR1C2, and AKR1C3 mRNA and protein but also reversed oxaliplatin resistance in S3 cells. Taken together, these results suggest that activation of the Nrf2/AKR1C axis may contribute to oxaliplatin resistance in S3 cells but that the IL-6 signaling pathway did not contribute to resistance. Manipulation of Nrf2/AKR1Cs activity may be useful for management of oxaliplatin-refractory gastric cancers.
Full-text · Article · Aug 2013 · Biochemical pharmacology
[Show abstract][Hide abstract]ABSTRACT: Histone deacetylases (HDACs), important epigenetic regulatory enzymes, can reduce cardiac hypertrophy and cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors remain unclear. The purposes of this study were to evaluate the effects of an HDAC inhibitor on systolic heart failure (HF) and investigate the potential mechanisms.
Echocardiographic, histologic, atrial natriuretic peptide (ANP), and Western blot measurements were performed in HF rats (isoproterenol 100mg/kg, subcutaneous injection) with and without orally administered (100mg/kg for 7 consecutive days) MPT0E014 (a novel HDAC inhibitor). Western blot, migration and proliferation assays were carried out on primary isolated cardiac fibroblasts with and without MPT0E014 (0.1 and 1μM) for 24h.
MPT0E014-treated HF rats (n=6) had better fraction shortening (48±2 vs. 33±4%, p=0.006) and smaller left ventricular end diastolic diameter (4.6±0.2 vs. 5.6±0.3mm, p=0.031) and systolic diameter (2.4±0.2 vs. 3.9±0.3mm, p=0.006) than HF (n=7) rats. MPT0E014-treated HF rats had lower ANP, cardiac fibrosis, and angiotensin II type I receptor (AT1R), transforming growth factor (TGF)-β, and CaMKIIδ protein levels compared to HF rats. MPT0E014 (at 1μM, but not 0.1μM) decreased the migration and proliferation of cardiac fibroblasts. MPT0E014 (0.1 and 1μM) decreased expression of the AT1R and TGF-β.
MPT0E014 improved cardiac contractility and attenuated structural remodeling in isoproterenol-induced dilated cardiomyopathy. The direct antifibrotic activity may have contributed to these beneficial effects.
No preview · Article · Aug 2013 · International journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: In previous research, we found α-enolase to be inversely correlated with progression-free and overall survival in lung cancer patients and detected α-enolase on the surface of lung cancer cells. Based on these findings, we hypothesized that surface α-enolase has a significant role in cancer metastasis and tested this hypothesis in the current study. We found that α-enolase was co-immunoprecipitated with urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen in lung cancer cells and interacted with these proteins in a cell-free dot blotting assay, which can be interrupted by α-enolase-specific antibody. α-Enolase in lung cancer cells co-localized with these proteins and was present at the site of pericellular degradation of extracellular matrix components. Treatment with antibody against α-enolase in vitro suppressed cell-associated plasminogen and matrix metalloproteinase activation, collagen and gelatin degradation, and cell invasion. Examination of the effect of treatment with shRNA plasmids revealed that down regulation of α-enolase decreases extracellular matrix degradation by and the invasion capacity of lung cancer cells. Adoptive transfer of α-enolase-specific antibody to mice resulted in accumulation of antibody in subcutaneous tumor and inhibited the formation of tumor metastasis in lung and bone. This study demonstrated that surface α-enolase promotes extracellular matrix degradation and invasion of cancer cells and that targeting surface α-enolase is a promising approach to suppress tumor metastasis.
[Show abstract][Hide abstract]ABSTRACT: Western blotting assay of citrullinated protiens in LLC cells. The whole cell lysate and membrane fraction of LLC cells immunoprecipitated (IP) with anti-mENO1 Ab were immunoblotted (IB) with anti-mENO1 or anti-citrulline Ab. -: cell lysate without IP.
[Show abstract][Hide abstract]ABSTRACT: Dot-blot analysis demonstrated the effect of ENO1 Ab on the interaction of ENO1, PLG, uPA and uPAR. After dotting respectively with plasminogen (PLG)(left panel), uPA (middle panel), or uPAR (right panel), together with ENO1 and OVA, the membranes were further incubated with soluble PLG (left), uPA (middle), and uPAR (right) in the presence of the isotype-control Ab, ENO1-specific Ab, control IgY or ENO1 IgY. The binding of dotted ENO1 to soluble PLG, uPA and uPAR were revealed by detecting with Ab against PLG (left), uPA (middle) and uPAR (right), respectively. OVA was used as a blotting control.