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781.
782.
Yamano N Higashida N Endo C Sakata N Fujishima S Maruyama A Higashihara T 《Marine biotechnology (New York, N.Y.)》2000,2(1):57-64
A psychrotrophic bacterium, strain Mct-9, which produced an N-acetylglucosamine-6-phosphate deacetylase, was isolated from a deep-seawater sample in the Mariana Trough. The Mct-9 strain
was identified as Alteromonas sp. The native enzyme had a molecular mass of 164,000 Da, and was predicted to be composed of four identical subunits with
molecular masses of 41,000 Da. The purified enzyme hydrolyzed N-acetylglucosamine (GlcNAc), GlcNAc-6-phosphate, and GlcNAc-6-sulfate. Considering the low K
m
and high k
cat
/K
m
for GlcNAc-6-phosphate, it probably acts as a GlcNAc-6-phosphate deacetylase in vivo. The enzyme was functional in the temperature
range of 5° to 70°C and displayed optimal activity at 55°C. The optimal temperature was higher than that of the deacetylase
from the mesophilic bacterium Vibrio cholerae non-O1. The characteristics of the GlcNAc-6-phosphate deacetylase from Alteromonas sp. are unique among psychrotrophs and psychrophiles, whose intracellular enzymes are mostly thermolabile.
Received May 6, 1999; accepted August 16, 1999. 相似文献
783.
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. 相似文献
784.
Sean D. Kodani Saavan Bhakta Sung Hee Hwang Svetlana Pakhomova Marcia E. Newcomer Christophe Morisseau Bruce D. Hammock 《Bioorganic & medicinal chemistry letters》2018,28(4):762-768
Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH. Inhibitors with a 6-fold increase of FAAH potency while maintaining high sEH potency were developed by optimization. Interestingly, compared to most FAAH inhibitors that inhibit through time-dependent covalent modification, t-TUCB and related compounds appear to inhibit FAAH through a time-independent, competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition. 相似文献
785.
786.
Quinazoline‐Based Hydroxamic Acids: Design,Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity
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Doan Thanh Hieu Duong Tien Anh Pham‐The Hai Le‐Thi‐Thu Huong Eun Jae Park Jeong Eun Choi Jong Soon Kang Phan Thi Phuong Dung Sang‐Bae Han Nguyen‐Hai Nam 《化学与生物多样性》2018,15(6)
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. 相似文献
787.
788.
The hallmarks of tumor tissue are not only genetic aberrations but also the presence of metabolic and oxidative stress as a result of hypoxia and lactic acidosis. The stress activates several prosurvival pathways including metabolic remodeling, autophagy, antioxidant response, mitohormesis, and glutaminolysis, whose upregulation in tumors is associated with a poor survival of patients, while their activation in healthy tissue with statins, metformin, physical activity, and natural compounds prevents carcinogenesis. This review emphasizes the dual role of stress response pathways in cancer and suggests the integrative understanding as a basis for the development of rational therapy targeting the stress response. 相似文献
789.
Dongdong Wang Pavel Uhrin Andrei Mocan Birgit Waltenberger Johannes M. Breuss Devesh Tewari Judit Mihaly-Bison Łukasz Huminiecki Rafał R. Starzyński Nikolay T. Tzvetkov Jarosław Horbańczuk Atanas G. Atanasov 《Biotechnology advances》2018,36(6):1586-1607
Cardiovascular diseases are a major cause of human death worldwide. Excessive proliferation of vascular smooth muscle cells contributes to the etiology of such diseases, including atherosclerosis, restenosis, and pulmonary hypertension. The control of vascular cell proliferation is complex and encompasses interactions of many regulatory molecules and signaling pathways. Herein, we recapitulated the importance of signaling cascades relevant for the regulation of vascular cell proliferation. Detailed understanding of the mechanism underlying this process is essential for the identification of new lead compounds (e.g., natural products) for vascular therapies. 相似文献
790.
Fabiana Rodrigues Silva Gasparin Fernando Olinto Carreño Juliana Moraes Mewes Eduardo Hideo Gilglioni Clairce Luzia Salgueiro Pagadigorria Maria Raquel Marçal Natali Karina Sayuri Utsunomiya Rodrigo Polimeni Constantin Amanda Tomie Ouchida Carlos Curti Ingrid C. Gaemers Ronald Petrus Johannes Oude Elferink Jorgete Constantin Emy Luiza Ishii-Iwamoto 《生物化学与生物物理学报:疾病的分子基础》2018,1864(7):2495-2509