Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.

Exploration of certain 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.

Several novel series of hydroxamic acids bearing 2-benzamidooxazole/thiazole (5a-g, 6a-g) or 2-phenylsulfonamidothiazole (8a-c) were designed and synthesized. The compounds were obtained straightforwards via a two step pathway, starting from commercially available ethyl 2-aminooxazole-4-carboxylate or ethyl 2-aminothiazole-4-carboxylate. Biological evaluation showed that these hydroxamic acids generally exhibited good cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer), with IC50 values in low micromolar range and comparable to that of SAHA. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range (0.010-0.131 µM) and some compounds (e.g 5f, IC50, 0.010 µM) were even more potent than SAHA (IC50, 0.025 µM) in HDAC inhibition. Representative compounds 6a and 8a appeared to arrest the SW620 cell cycle at G2 phase and significantly induced both early and late apoptosis of SW620 colon cancer cells. Docking experiments on HDAC2 and HDAC6 isozymes revealed favorable interactions at the tunnel of the HDAC active site which positively contributed to the inhibitory activity of synthesized compound. The binding affinity predicted by docking program showed good correlation with the experimental IC50 values. This study demonstrates that simple 1,3-oxazole- and 1,3-thiazole-based hydroxamic acids are also promising as antitumor agents and HDAC inhibitors and these results should provide valuable information for further design of more potent HDAC inhibitors and antitumor agents.

New Acetohydrazides Incorporating 2-Oxoindoline and 4-Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity.

In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.

Manure management and pollution levels of contract and non-contract livestock farming in Vietnam.

In analyzing contract farming of livestock production, many studies have focused on the economic aspect. This paper offers the environmental issue by investigating manure management and pollution levels of contract farming (CF) and non-contract farming (NCF) livestock producers in Vietnam. By surveying 270 pig farms and applying logit model, we found that commercial pigpen type of CF reduces the probability of manure separation, while larger garden area and knowledge of composting increase it. By analyzing the wastewater samples collected from 59 farms and employing nearest neighbor matching technique, this paper indicated that CF reduces the pollutants' concentrations in effluents. Using OLS regression models, we found out that manure separation contributes to a reduction in nutrient matters, while biogas plant or combination of biogas plant and stabilization ponds helps to diminish organic matters. The study results suggest that the government should regulate the minimum required land area for installation of the combined manure treatment plants (MTPs). Additionally, to recycle manure and improve nutrient matters in effluent, advanced technologies for separating solid manure are extremely necessary for CF producers. Furthermore, we recommend the government to build mechanisms to compel agribusiness firms engaging in their liability for the environmental side effects caused by their CF producers.

Novel 3,4-dihydro-4-oxoquinazoline-based acetohydrazides: Design, synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N'-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH3, 4-OCH3, and 4-N(CH3)2, were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH3 substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most of the compounds, in this series, especially compounds 5c, 5b and 5h, also significantly activated caspase-3 activity. Among these, compound 5c displayed 1.61-fold more potent than PAC-1 as caspase-3 activator. Cell cycle analysis showed that compounds 5b, 5c, and 5h significantly arrested the cell cycle in G1 phase. Further apoptotic studies also demonstrated compounds 5b, 5c, and 5h as strong apoptotic cell death inducers. The docking simulation studies showed that these compounds could activate procaspase via chelating Zn2+ ion bound to the allosteric site of the zymogen.

(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity.

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.

Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity.

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10-0.16 µm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29-3.67 µm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21-0.38 µm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents.

BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. CONCLUSIONS: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

N'-[(E)-Arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)-acetohydrazides: Synthesis and Evaluation of Caspase Activation Activity and Cytotoxicity.

In our search for novel small cytotoxic molecules potentially activating procaspase-3, we have designed and synthesized a series of novel N'-[(E)-arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)acetohydrazides (5, 6). Biological evaluation revealed that seven compounds, including 5h, 5j, 5k, 5l, 5n, 6a, and 6b, exhibited moderate to strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Among these compounds, two most cytotoxic compounds (5h and 5j) displayed from 3- up to 10-fold higher potency than PAC-1 and 5-FU in three cancer cell lines tested. Three compounds 5j, 5k, and 5n were also found to display better caspases activation activity in comparison to PAC-1. Especially, compound 5k activated the level of caspases activity by 200% higher than that of PAC-1. From this study, three compounds 5j, 5k, and 5n could be considered as potential leads for further design and development of caspase activators and anticancer agents.

Novel Hydroxamic Acids Incorporating 1-((1H-1,2,3-Triazol-4-yl)methyl)- 3-substituted-2-oxoindolines: Synthesis, Biological Evaluation and SAR Analysis.

BACKGROUND: Histone deacetylases (HDAC) enzymes are emerging as potential targets for cancer treatments. In this study, several series of novel hydroxamic acids incorporating 1-((1H- 1,2,3-triazol-4-yl)methyl)-3-substituted-2-oxoindolines were explored. METHODS: The compounds were designed using Autodock Vina program, then synthesized and evaluated in vitro and in silico for their inhibitory activity against HDACs. The cytotoxicity was measured by SRB method. The enzyme inhibitory effects of the compounds were evaluated by the fluorescent assay. RESULTS: Biological evaluation showed that these hydroxamic acids were generally cytotoxic against four human cancer cell lines (SW620, colon; PC-3, prostate; AsPC-1, pancreas; NCI-H23, lung). Several compounds, e.g. 7g, 11c, and 11g, displayed up to 10-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. The synthesized compounds were also comparably potent to SAHA in inhibiting HDAC2. In particular, compound 11c displayed potential inhibitory effects against HDAC1, HDAC2, HDAC6, and HDAC8 with comparable or slightly higher potency than SAHA. Docking results on four class I and IIB isoenzymes indicated that these compounds tightly bound to HDACs at the active site with binding affinities much higher than that of SAHA. Finally, chemo-informatics approaches were employed to assess the pharmacokinetic and toxicity profiles of 7g and 11c. We identified degradation via phase II metabolism and toxicity two of the most serious problems that need further optimization. CONCLUSION: Taking altogether our findings are encouraging and current hydroxamate derivatives are worth being considered as potential HDAC inhibitors and could be useful for further research on the development of new anti-cancer agents.

Quinazoline-Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity.

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a - 4i, 6a - 6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g - 4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.

Design, synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R2 ∼ 95%) with experimental results.

Novel N-hydroxybenzamides incorporating 2-oxoindoline with unexpected potent histone deacetylase inhibitory effects and antitumor cytotoxicity.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized two series of novel N-hydroxybenzamides incorporating 2-oxoindolines (4a-g, 6a-g). Biological evaluation showed that these benzamides potently inhibited HDAC2 with IC50 values in sub-micromolar range. In three human cancer cell lines the synthesized compounds were up to 4-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel and simple N-hydroxybenzamides are potential for further development as anticancer agents and further investigation of similarly simple N-hydroxybenzamides should be warranted to obtain more potent HDAC inhibitors.

Protective effect of Tetracera scandens L. leaf extract against CCl

Objective: To investigate the protective potential of ethanolic extracts of Tetracera scandens L. (T. scandens) against CCl

Allergic rhinitis and its impact on asthma update (ARIA 2008)--western and Asian-Pacific perspective.

The prevalence of allergic diseases such as allergic rhinitis (AR) and asthma is markedly increasing worldwide as societies adopt western life styles. Allergic sensitization is an important risk factor for asthma and AR, and asthma often co-exists with AR. An estimated 300 million people worldwide have asthma, about 50% of whom live in developing countries and about 400 million people suffer from AR. Yet, AR is often under-diagnosed and under-treated due to a lack of appreciation of the disease burden and its impact on quality of life, as well as its social impact at school and at the workplace. However, AR with or without asthma is a huge economic burden. Thus, there was clearly a need for a global evidence-based document which would highlight the interactions between the upper and lower airways including diagnosis, epidemiology, common risk factors, management and prevention. The Allergic Rhinitis and its Impact on Asthma (ARIA) document was first published in 2001 as a state-of-the-art guideline for the specialist, the general practitioner and other health care professionals. Subsequent new evidence regarding the pathomechanisms, new drugs and increased knowledge have resulted in the publication of the ARIA 2008 update. The present review summarizes the ARIA update with particular emphasis on the current status of AR and asthma in the Asia-Pacific region and discusses the Western and Asian perspective.