Search

Indolizidine and quinolizidine derivatives are readily assembled from L-proline or (±)-pipecolic acid and β-ketoaldehydes via a decarboxylative annulation process. These reactions are promoted by acetic acid and involve azomethine ylides as reactive intermediates.

In the past, several microtubule targeting agents (MTAs) have been developed into successful anticancer drugs. However, the usage of these drugs has been limited by the acquisition of drug resistance in many cancers. Therefore, there is a constant demand for the development of new therapeutic drugs. Here we report the discovery of 5-5 (3-cchlorophenyl)-N-(3-pyridinyl)-2-furamide (CPPF), a novel microtubule targeting anticancer agent. Using both 2D and 3D culture systems, we showed that CPPF was able to suppress the proliferation of diverse cancer cell lines. In addition, CPPF was able to inhibit the growth of multidrug-resistant cell lines that are resistant to other MTAs, such as paclitaxel and colchicine. Our results showed that CPPF inhibited growth by depolymerizing microtubules leading to mitotic arrest and apoptosis. We also confirmed CPPF anticancer effects in vivo using both a mouse xenograft and a two-step skin cancer mouse model. Using established zebrafish models, we showed that CPPF has low toxicity in vivo. Overall, our study proves that CPPF has the potential to become a successful anticancer chemotherapeutic drug.

Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anti-cancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach.

Adipogenesis is a key driver of the expansion of adipose tissue mass that causes obesity. Hirsutenone (HST) is an active botanical diarylheptanoid present in Alnus species. In this study, we evaluated the effects of HST on adipogenesis, its mechanisms of action and the molecular targets involved. Using Oil Red O staining, we observed that HST dose-dependently suppresses lipid accumulation during adipogenesis in 3T3-L1 preadipocytes, concomitant with a decrease in peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and fatty acid synthase (FAS) protein expression. This inhibitory effect was largely limited to the early stage of adipogenesis, which includes mitotic clonal expansion (MCE), as evidenced by delayed cell cycle entry of preadipocytes from G1 to S phase. Furthermore, the regulation of MCE was accompanied by suppression of phosphatidylinositol 3-kinase (PI3K) and extracellular-regulated kinase (ERK) activity. HST was also shown to bind directly to PI3K and ERK1 in a non-ATP competitive manner. Our results suggest that HST attenuates adipogenesis by directly targeting PI3K and ERK during MCE in 3T3-L1 preadipocytes, underscoring the potential therapeutic application of HST in preventing obesity.

In this study, we have synthesized novel water soluble derivatives of natural compound aloe emodin 4(a-j) by coupling with various amino acid esters and substituted aromatic amines, in an attempt to improve the anticancer activity and to explore the structure-activity relationships. The structures of the compounds were determined by (1) H NMR and mass spectroscopy. Cell growth inhibition assays revealed that the aloe emodin derivatives 4d, 4f, and 4i effectively decreased the growth of HepG2 (human liver cancer cells) and NCI-H460 (human lung cancer cells) and some of the derivatives exhibited comparable antitumor activity against HeLa (Human epithelial carcinoma cells) and PC3 (prostate cancer cells) cell lines compared to that of the parent aloe emodin at low micromolar concentrations.

Although specific compounds found in some East Asian traditional medicines have been shown to exhibit bioactive properties, their molecular mechanisms of action remain elusive. The bark of the Alnus species has been used for the treatment of various pathological conditions including hemorrhage, alcoholism, fever, diarrhea, skin diseases, inflammation, and cancer in East Asia for centuries. In this study, we show that hirsutenone, a bioactive compound in Alnus japonica, exhibits anti-cancer effects against prostate cancer through a direct physical inhibition of Akt1/2. Hirsutenone suppressed anchorage-dependent and independent cell growth of PC3 and LNCaP human prostate cancer cells. Annexin V and Propidium iodide (PI) staining results demonstrated that hirsutenone strongly induces apoptotic cell death in both PC3 and LNCaP cells. Furthermore, treatment of hirsutenone attenuated phosphorylation of mammalian target of rapamycin (mTOR), a downstream substrate of Akt, without affecting Akt phosphorylation. Kinase and pull-down assay results clearly show that hirsutenone inhibits Akt1 and 2 by direct binding in an adenosine triphosphate (ATP)-noncompetitive manner in vitro and ex vivo. Our results show that hirsutenone suppresses human prostate cancer by targeting Akt1 and 2 as a key component to explain for anti-cancer activity of Alnus species. © 2014 Wiley Periodicals, Inc.

Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprevention and chemotherapy. Herein we report that eupafolin, a natural compound found in common sage, inhibited proliferation of prostate cancer cells. Protein content analysis indicated that phosphorylation of Akt and its downstream kinases was inhibited by eupafolin treatment. Pull-down assay and in vitro kinase assay results indicated that eupafolin could bind with PI3-K and attenuate its kinase activity. Eupafolin also exhibited tumor suppressive effects in vivo in an athymic nude mouse model. Overall, these results suggested that eupafolin exerts antitumor effects by targeting PI3-K.

Mitogen- and stress-activated kinase 1 (MSK1) is a nuclear serine/threonine protein kinase that acts downstream of both extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in response to stress or mitogenic extracellular stimuli. Increasing evidence has shown that MSK1 is closely associated with malignant transformation and cancer development. MSK1 should be an effective target for cancer chemoprevention and chemotherapy. However, very few MSK1 inhibitors, especially natural compounds, have been reported. We used virtual screening of a natural products database and the active conformation of the C-terminal kinase domain of MSK1 (PDB id 3KN) as the receptor structure to identify chrysin and its derivative, compound 69407, as inhibitors of MSK1. Compared with chrysin, compound 69407 more strongly inhibited proliferation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells with lower cytotoxicity. Western blot data demonstrated that compound 69407 suppressed phosphorylation of the MSK1 downstream effector histone H3 in intact cells. Knocking down the expression of MSK1 effectively reduced the sensitivity of JB6 P+ cells to compound 69407. Moreover, topical treatment with compound 69407 before TPA application significantly reduced papilloma development in terms of number and size in a two-stage mouse skin carcinogenesis model. The reduction in papilloma development was accompanied by the inhibition of histone H3 phosphorylation at Ser10 in tumors extracted from mouse skin. The results indicated that compound 69407 exerts inhibitory effects on skin tumorigenesis by directly binding with MSK1 and attenuates the MSK1/histone H3 signaling pathway, which makes it an ideal chemopreventive agent against skin cancer. Cancer Prev Res; 7(1); 74–85. ©2013 AACR.

Chrysin (5,7-dihydroxyflavone), a natural flavonoid widely distributed in plants, reportedly has chemopreventive properties against various cancers. However, the anticancer activity of chrysin observed in in vivo studies has been disappointing. Here, we report that a chrysin derivative, referred to as compound 69407, more strongly inhibited EGF-induced neoplastic transformation of JB6 P+ cells compared with chrysin. It attenuated cell cycle progression of EGF-stimulated cells at the G1 phase and inhibited the G1/S transition. It caused loss of retinoblastoma phosphorylation at both Ser-795 and Ser-807/811, the preferred sites phosphorylated by Cdk4/6 and Cdk2, respectively. It also suppressed anchorage-dependent and -independent growth of A431 human epidermoid carcinoma cells. Compound 69407 reduced tumor growth in the A431 mouse xenograft model and retinoblastoma phosphorylation at Ser-795 and Ser-807/811. Immunoprecipitation kinase assay results showed that compound 69407 attenuated endogenous Cdk4 and Cdk2 kinase activities in EGF-stimulated JB6 P+ cells. Pulldown and in vitro kinase assay results indicated that compound 69407 directly binds with Cdk2 and Cdk4 in an ATP-independent manner and inhibited their kinase activities. A binding model between compound 69407 and a crystal structure of Cdk2 predicted that compound 69407 was located inside the Cdk2 allosteric binding site. The binding was further verified by a point mutation binding assay. Overall results indicated that compound 69407 is an ATP-noncompetitive cyclin-dependent kinase inhibitor with anti-tumor effects, which acts by binding inside the Cdk2 allosteric pocket. This study provides new insights for creating a general pharmacophore model to design and develop novel ATP-noncompetitive agents with chemopreventive or chemotherapeutic potency. Background: Binding to the ATP site results in poor selectivity; therefore, development of ATP-noncompetitive inhibitors is needed. Results: A modified chrysin with anticancer activity targets Cdks and binds to a Cdk2 allosteric site, not the ATP pocket. Conclusion: Modified chrysin is a novel ATP-noncompetitive inhibitor. Significance: This pharmacophore model might provide insights for the development of new ATP-noncompetitive agents.

cope Ginger exerts protective effects on obesity and its complications. Our objectives here are to identify bioactive compounds that inhibit adipogenesis and lipid accumulation in vitro, elucidate the anti-obesity effect of gingerenone A (GA) in diet-induced obesity (DIO), and investigate whether GA affects adipose tissue inflammation (ATI). Methods and results Oil red O staining showed that GA had the most potent inhibitory effect on adipogenesis and lipid accumulation in 3T3-L1 cells among ginger components tested at a single concentration (40 μM). Consistent with in vitro data, GA attenuates DIO by reducing fat mass in mice. This was accompanied by a modulation of fatty acid metabolism via activation of AMP-activated protein kinase (AMPK) in vitro and in vivo. Additionally, GA suppressed ATI by inhibiting macrophage recruitment and downregulating pro-inflammatory cytokines. Conclusion These results suggest that GA may be used as a potential therapeutic candidate for the treatment of obesity and its complications by suppressing adipose expansion and inflammation.

Patulin is a fungal mycotoxin of Aspergilus and Penicillium that is commonly found in rotting fruits and exerts its potential toxic effect mainly by reactive oxygen species (ROS) generation. However, the effect of patulin on cancer cells as well as its intracellular mechanism has been controversial and not clearly defined yet. In this study, patulin was found to induce G1/S accumulation and cell growth arrest accompanied by caspase-3 activation, PARP cleavage and ATF3 expression in human colon cancer cell line HCT116. Ser/Thr phosphorylation of a transcription factor, EGR-1, was increased while its expression did not change upon patulin treatment to the cells. Knockdown of ATF3 and EGR-1 using their respective siRNAs showed EGR-1 dependent ATF3 expression. Moreover, treatment of the cells with antioxidants N-acetylcysteine (NAC) and glutathione (GSH) revealed that patulin induced ATF3 expression and apoptosis were dependent on ROS generation. ATF3 expression was also increased by patulin in other colorectal cancer cell types, Caco2 and SW620. Collectively, our data present a new anti-cancer molecular mechanism of patulin, suggesting EGR-1 and ATF3 as critical targets for the development of anti-cancer chemotherapeutics. In this regard, patulin could be a candidate for the treatment of colorectal cancers.

In a program to identify new anti-ulcer compounds, a series of novel substituted thiazolidinone derivatives 5(a–j) were synthesized and screened for their in vitro H+, K+-ATPase inhibitory activity. The synthesized compounds were characterized by nuclear magnetic resonance (1H-NMR), liquid chromatography-mass spectrometry (LCMS) and fourier transform infrared (FTIR) analysis. We have briefly investigated the structure–activity relation (SAR) studies and reveal that the nature of position of the fluorine atom influences the anti-ulcer activity. Among the synthesized compounds 5b, 5c and 5e showed 4 and 10-fold higher H+, K+-ATPase activity when compared with those of other derivatives 5a, 5f, 5g and 5j, respectively. H+, K+-ATPase activity of 5b, 5c and 5e were comparable with those of known H+, K+-ATPase blocker lansoprazole which is a potential anti-ulcer drug.

A series of novel thioxothiazolidin-4-one derivatives 5(a–g) were synthesized by the coupling of different amines containing aliphatic, substituted aromatic, and heterocyclic moieties, such as oxadiazol, pyrazole, isoxazole, and piperazine with 2-(5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid. All compounds were characterized by 1H NMR, LCMS, FTIR and elemental analysis. In this study, we investigated the possibility that these novel thioxothiazolidin-4-one derivatives 5(a–g) inhibits tumor growth and tumor induced angiogenesis using mouse Ehrlich Ascites Tumor (EAT) as a model system. Our results demonstrated that the compounds significantly reduced ascites tumor volume, cell number, and increased the life span of EAT-bearing mice. In addition, the compounds manifested strong antiangiogenic effects and suppressed tumor induced endothelial proliferation in the mice peritoneum. From our findings, it is noted that the derivatives 5(a–e) may be possible candidates for anticancer therapy with the ability to inhibit tumor angiogenesis and tumor cell proliferation.

A series of N-substituted thiazolidinone derivatives 5(a-j) was synthesized in good yield. All the compounds were screened for their in vitro H(+), K(+)-ATPase inhibitory activity. The structures of the synthesized compounds were confirmed by the spectral data. Compounds 5d, 5e, 5f and 5c showed potential H(+), K(+)-ATPase blocking activities, when compared to standard drug Lansoprazole. Structure-activity relationship studies, with various chemical groups, revealed that position and nature of the substitution on the N-thiazolidinones are crucial for H(+), K(+)-ATPase inhibitory activity.

The compound, 7-chloro-5-cyclopropyl-9-methyl-10-(2-piperidin-1-yl-ethyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a, d] cyclohepten-11-one, C22H26N5ClO, crystallizes in the triclinic space group Pī with cell parameters a = 8.918(7) A, b = 9.297(7) A, c = 14.184(8) A, V = 1095.98(1) A3 and Z = 2. The final residual factor R 1 = 0.0451. The structure exhibits intermolecular hydrogen bonds. The 2-piperidin-1-yl-ethyl ring adopts a chair conformation. The starting material used to synthesize the title compound is the intermediate compound of well known anti-HIV drug Nevirapine hence the title compound is having biological importance and hence this crystal structure will helps to structural characterization of the molecule and also for the molecular modeling it will helps for biological study. The title compound 7-chloro-5-cyclopropyl-9-methyl-10-(2-piperidin-1-yl-ethyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a, d] cyclohepten-11-one was synthesized by condensation of 7-chloro-5-cyclopropyl-9-methyl-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a, d] cyclohepten-11-one with 1-(2-chloro-ethyl)-piperidine hydrochloride in presence of anhydrous powdered potassium carbonate as base using N,N-dimethyl formamide as solvent and its crystal structure determined. The title compound derived from bioactive molecule and it is also having biological importance hence this crystal structure will helps for the structural characterization and the biological study of the novel molecule.

The title compound 7-chloro-5-cyclopropyl-9-methyl-10-(4-nitro-benzyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo [a,d] cyclohepten-11-one was synthesized and characterized spectroscopically and finally confirmed by X-ray diffraction study. The title compound crystallizes in the monoclinic space group P21/c with cell parameters a = 11.644(8) A, b = 14.826(1) A, c = 15.919(8) A, α = 90°, β = 130.377(4)°,γ = 90°, V = 2093.5(2) A3, and Z = 4. The NO2 group in the ring is almost in the same plane of the nitrobenzyl ring. The structure exhibits neither inter nor intra molecular hydrogen bonding.

A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 3(a-e) were synthesized by nucleophilic substitution reaction of 1-benzhydryl-piperazine with different sulfonyl chlorides and were characterized by 1H NMR, LC/MS, FTIR and elemental analysis. In the present study, the compounds 3(a-e) exhibited in vivo inhibition of Ehrlich ascites tumor (EAT) cell growth and increased the Median Survival Time (MST) and %ILS of EAT bearing mice. Further treatment of derivatives in vivo resulted in reduction of EAT cell number and ascites formation. The efficacy of the derivatives to inhibit the angiogenesis in vivo was evaluated in tumor bearing mice peritoneum and chorio allantoic membrane (CAM) model. The compounds suppressed the blood vessel formation in vivo in mice peritoneum and in CAM. Among the compounds studied, 3e demonstrated highest tumor inhibitory and anti-angiogenic effects against mouse tumor. However, this phenomenon needs detailed investigation.

In the course of structure-activity relationship studies and to explore the antiproliferative effect associated with the hydantoin framework, diversely substituted several diazaspiro hydantoins were synthesized. Variation in the functional group at N-terminal of the hydantoin ring and coupling of different substituted aromatic acids in 4-aminocyclohexanone ring led to three sets of compounds. The antiproliferative effect of the compounds was evaluated in vitro using the MTT colorimetric method against one normal cell line (NDF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, some compounds exhibited interesting growth inhibitory effects against all four cell lines. From the SAR studies, it reveals that, the substitution at N-terminal in hydantoin ring plays key role in the antiproliferative activity.

A series of novel, potent, and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N-substituted morpholine Arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimer's diseases. The ester group of arecoline (which is reported as muscarinic agonist) has been replaced by N-substituted morpholine ring. The structure activity relationship reveals that the electron donating 4-substituted sulfonyl derivatives (9a, 9b, 9c, and 9e) on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor binding 50- to 80-fold greater than the corresponding arecoline. Other derivatives also showed considerable M1 receptor binding affinity. (C) 2008 Elsevier Ltd. All rights reserved.

A series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a-d) and 7 (a-g) were synthesized with different substituted aromatic sulfonyl chlorides (R-SO(2)-Cl) and alkyl halides (R-X) and were characterized by (1)H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evaluated for their cell antiproliferation activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The antiproliferative effects of the synthesised compounds were tested against viable human skin fibroblast cell line and carcinoma cell lines namely HeLa cells, HT-29 cells, MCF-7 cells, HepG-2 cells by adopting positive and negative control. The importance of the nitro group on thiazolidinone moiety was confirmed and it was concluded that the fourth position of the substituted aryl ring plays a dominant role and was responsible for the antiproliferative activity. Among the synthesized compounds only 6a, 7e and 7g have potent antiproliferative activity on all the carcinoma cell lines tested.

The compound 7-chloro-5-cyclopropyl-9-methyl-10-(2-nitro-4-trifluromethyl-phenyl)- 5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a,d]cyclohepten-11-one, C22H15N5O3F3Cl, crystallizes in the monoclinic crystal class under the space group P21/c with cell parameters a = 16.595(7) A, b = 8.775(7) A, c = 14.973(1) A, β = 97.465(4), V = 2161.9(3) A3, Z = 4. The structure was solved by direct methods using SHELXS-97, and refined using SHELXL-97. The final residual factor is R1 = 0.0604 for 4116 reflections and 342 parameters. The molecular structure exhibits intramolecular hydrogen bond of the type C–H · · · O.

A novel series of trisubstituted benzimidazole and its precursors ( 3 – 7 ) were synthesised and characterized by using 1 H NMR, LC/MS, FTIR and elemental analysis techniques. The title compounds were evaluated for inhibition against MDA-MB-231 breast cancer cell proliferation. The results revealed that the compound N -(4-cyano-3-(trifluoromethyl) phenyl)-4-fluoro-3-nitrobenzamide ( 3 ) was the potent inhibitor.

The title compound, 1-benzhydryl-4-methanesulfonyl-piperazine, was synthesized by the nucleophilic substitution of 1-benzhydryl-piperazine with methyl sulfonyl chloride. The product obtained was characterized by spectroscopic techniques, and the structure was investigated by X-ray crystallography. The compound crystallizes in the monoclinic crystal class in the space group P21/c with cell parameters a = 9.5820(4) A○, b = 16.8150(12) A○, c = 13.5280(8) A○, β = 127.270(5)°, and V = 1734.5(2)A○ 3 for Z = 4. The structure reveals that the piperazine ring is in a chair conformation. There is a large discrepancy around the bond angles of the piperazine N atoms. The geometry around the S atom is distorted tetrahedral.

A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 7(a-e) were designed by a nucleophilic substitution reaction of 1-benzhydryl-piperazine with various sulfonyl chlorides and characterized by 1H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. Our research is focused on identifying synthetically occurring chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis. The title compounds were evaluated for their efficacy in inhibiting MDA-MB-231 breast cancer cell proliferation. Compound 1-benzhydryl-4-(4-tert-butyl-benzenesulfonyl)-piperazine (7d) showed significant inhibitory activity.

1-Benzenesulfonyl-4-benzhydryl-piperazine was synthesized from 1-benzhydryl piperazine with benzenesulfonyl chloride. The title compound, C23H24N2O2S, was synthesized and the structure was investigated by X-ray crystallography. The compound crystallizes in the monoclinic crystal class in the space group P21/c with cell parameters a = 13.2390(10) A, b = 9.1960(7) A, c = 18.5810(16) A, β = 110.873(3)°, and Z = 4. The piperazine ring in the structure is in a chair conformation. The geometry around the S atom is distorted tetrahedral. The structure exhibits an intermolecular hydrogen bond of the type C‒H · O.

Adipogenesis is a key driver of the expansion of adipose tissue mass that causes obesity. Hirsutenone (HST) is an active botanical diarylheptanoid present in Alnus species. In this study, we evaluated the effects of HST on adipogenesis, its mechanisms of action and the molecular targets involved. Using Oil Red O staining, we observed that HST dose-dependently suppresses lipid accumulation during adipogenesis in 3T3-L1 preadipocytes, concomitant with a decrease in peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and fatty acid synthase (FAS) protein expression. This inhibitory effect was largely limited to the early stage of adipogenesis, which includes mitotic clonal expansion (MCE), as evidenced by delayed cell cycle entry of preadipocytes from G1 to S phase. Furthermore, the regulation of MCE was accompanied by suppression of phosphatidylinositol 3-kinase (PI3K) and extracellular-regulated kinase (ERK) activity. HST was also shown to bind directly to PI3K and ERK1 in a non-ATP competitive manner. Our results suggest that HST attenuates adipogenesis by directly targeting PI3K and ERK during MCE in 3T3-L1 preadipocytes, underscoring the potential therapeutic application of HST in preventing obesity.

Although specific compounds found in some East Asian traditional medicines have been shown to exhibit bioactive properties, their molecular mechanisms of action remain elusive. The bark of the Alnus species has been used for the treatment of various pathological conditions including hemorrhage, alcoholism, fever, diarrhea, skin diseases, inflammation, and cancer in East Asia for centuries. In this study, we show that hirsutenone, a bioactive compound in Alnus japonica, exhibits anti-cancer effects against prostate cancer through a direct physical inhibition of Akt1/2. Hirsutenone suppressed anchorage-dependent and independent cell growth of PC3 and LNCaP human prostate cancer cells. Annexin V and Propidium iodide (PI) staining results demonstrated that hirsutenone strongly induces apoptotic cell death in both PC3 and LNCaP cells. Furthermore, treatment of hirsutenone attenuated phosphorylation of mammalian target of rapamycin (mTOR), a downstream substrate of Akt, without affecting Akt phosphorylation. Kinase and pull-down assay results clearly show that hirsutenone inhibits Akt1 and 2 by direct binding in an adenosine triphosphate (ATP)-noncompetitive manner in vitro and ex vivo. Our results show that hirsutenone suppresses human prostate cancer by targeting Akt1 and 2 as a key component to explain for anti-cancer activity of Alnus species.

Phosphatase and tensin homolog (PTEN) loss or mutation consistently activates the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway, which contributes to the progression and invasiveness of prostate cancer. Furthermore, the PTEN/PI3-K/Akt and Ras/MAPK pathways cooperate to promote the epithelial-mesenchymal transition (EMT) and metastasis initiated from prostate stem/progenitor cells. For these reasons, the PTEN/PI3-K/Akt pathway is considered as an attractive target for both chemoprevention and chemotherapy. Herein we report that eupafolin, a natural compound found in common sage, inhibited proliferation of prostate cancer cells. Protein content analysis indicated that phosphorylation of Akt and its downstream kinases was inhibited by eupafolin treatment. Pull-down assay and in vitro kinase assay results indicated that eupafolin could bind with PI3-K and attenuate its kinase activity. Eupafolin also exhibited tumor suppressive effects in vivo in an athymic nude mouse model. Overall, these results suggested that eupafolin exerts antitumor effects by targeting PI3-K.

The third author's name was spelled incorrectly. The correct name is: N.R. Thimmegowda. The correct citation is: Kim S-O, Sakchaisri K, Thimmegowda NR, Soung NK, Jang J-H, et al. (2013) STK295900, a Dual Inhibitor of Topoisomerase 1 and 2, Induces G2 Arrest in the Absence of DNA Damage. PLoS ONE 8(1): e53908. doi:10.1371/journal.pone.0053908

A series of novel substituted 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine benzamides 9(a-h) were synthesized to determine their antibacterial and antifungal activities as well as possible structure-activity relationships (SARs) to improve therapeutic efficacy. The pyrazol-5-amine benzamides were screened for their antibacterial activity against standard strains of Gram-positive (Streptococcus pyogenes NCIM 2608, Staphylococcus aureus ATCC 29737, Bacillus subtilis NCIM 2010) and Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 20852, Klebsiella pneumoniae MTCC 618) bacteria by using streptomycin as positive control. They were also tested for their antifungal activities against mycotoxic strains of Fusarium verticillioides, Aspergillus ochraceous, Aspergillus flavus, Alternaria alternata, and Penicillium chrysogenum using nystatin as positive control. Among the synthesized compounds, 9d, 9g, and 9h showed potent antimicrobial activities.

To study the structure activity relationship (SAR) on the cytotoxic activity and probe the structural requirement for the potent antitumor activity, a series of novel diazaspiro bicyclo hydantoin derivatives were designed and synthesized. Their structures were confirmed by H-1 NMR, LCMS and IR analyses. The antiproliferative effect of these compounds were determined against human leukemia, K562 (chronic myelogenous leukemia) and CEM (T-cell leukemia) cells using trypan blue and MTT assay, and the SAR associated with the position of N-terminal substituents in diazaspiro bicyclo hydantoin have also been discussed. It has been observed that these compounds displayed strong, moderate and weak cytotoxic activities. Interestingly, compounds having electron withdrawing groups at third and fourth position of the phenyl ring displayed selectively cytotoxic activities to both the cell lines tested with IC50 value lower than 50 mu M. In addition, the cytotoxic activities of the compounds 7(a-o) bearing the substituents at N-3 position of diazaspiro bicyclo hydantoin increases in the order alkene > ester > ether and plays an important role in determining their antitumor activities. The position and number of substituents in benzyl group attached to N-8 of diazaspiro bicyclo hydantoin nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.

In order to explore the antiproliferative effect associated with the piperazine framework, several 1-benzhydrylpiperazine derivatives 8(a-d), 9(a-d) and 10(a-h) were synthesized. Variation in the functional group at N-terminal of the piperazine led to three sets of compounds, bearing the sulfonyl, amide and thiourea, respectively. Their chemical structures were confirmed by (1)H NMR, LCMS, IR and elemental analysis. The antiproliferative effect of the compounds were evaluated in vitro using the MTT colorimetric method against one normal cell line (NF-103 skin fibroblast cells) and four human cancer cell lines (MCF-7 breast carcinoma cell line, HepG-2 hepatocellular carcinoma cell line, HeLa cervix carcinoma cell line and HT-29 colon carcinoma cell line) for the time period of 24 h. Among the series, four compounds exhibited interesting growth inhibitory effects against all four cell lines.

A series of tricyclic dipyrido diazepinone derivatives 6(a-f) bearing different substituents at the tenth position of diazepinone ring were designed and are characterized by 1H NMR, FTIR and X-Ray crystallography studies. The synthesised derivatives are tested in-vitro phospholipase A2 (PLA2) enzyme inhibitory activity and in-vivo anti-inflammatory activity against purified group I and group II PLA2 enzymes from the snake venom and human pleural fluid. Compounds bearing aromatic ring with different substituents at different positions shown varied specificity. The 6f derivative with strong electron withdrawing nitro (-NO2) and trifluoromethyl (-CF3) groups at ortho and para positions respectively shown greater inhibitory activity. Inhibitory effect of the compound appeared to be direct interaction with active site and likely competes with substrates as supported by substrate dependent and calcium independent assays. The IC50 value of potent PLA2 inhibitor 6f was 22.1 microM and showed similar potency in the neutralization of in vivo PLA2 induced mouse paw edema and hemolytic activity.

In the title compound, C15H13ClN4O, which is a chloro derivative of the drug Nevirapine, the diazepine ring is in a twisted boat conformation. The pyridine rings fused to the diazepine fragment form a dihedral angle of 58.44 (10)° and the molecule adopts a butterfly shape. The molecules are joined via N—H...N hydrogen bonding into polymeric chains down the b axis. All weaker C—H...O interactions involve the carbonyl O atom as acceptor.