scholarly journals Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 333 ◽  
Author(s):  
Bingbing Zhang ◽  
Guangsheng Shan ◽  
Yinying Zheng ◽  
Xiaolin Yu ◽  
Zhu-Wei Ruan ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Structural Similarity ◽  
Biological Evaluation ◽  
Histone Deacetylation ◽  
Marine Natural Product ◽  
Class I ◽  
Side Chain ◽  
Biological Assays ◽  
Chain Unit ◽  
Psammaplin A

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.

scholarly journals Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension

2016 ◽  
Vol 311 (1) ◽  
pp. L124-L134 ◽  
Author(s):  
Eva Nozik-Grayck ◽  
Crystal Woods ◽  
Robert S. Stearman ◽  
Sujatha Venkataraman ◽  
Bradley S. Ferguson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hdac Inhibitors ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Histone Deacetylation ◽  
Class I ◽  
Extracellular Superoxide Dismutase ◽  
Pulmonary Arterial

Epigenetic mechanisms, including DNA methylation and histone acetylation, regulate gene expression in idiopathic pulmonary arterial hypertension (IPAH). These mechanisms can modulate expression of extracellular superoxide dismutase (SOD3 or EC-SOD), a key vascular antioxidant enzyme, and loss of vascular SOD3 worsens outcomes in animal models of pulmonary arterial hypertension. We hypothesized that SOD3 gene expression is decreased in patients with IPAH due to aberrant DNA methylation and/or histone deacetylation. We used lung tissue and pulmonary artery smooth muscle cells (PASMC) from subjects with IPAH at transplantation and from failed donors (FD). Lung SOD3 mRNA expression and activity was decreased in IPAH vs. FD. In contrast, mitochondrial SOD (Mn-SOD or SOD2) protein expression was unchanged and intracellular SOD activity was unchanged. Using bisulfite sequencing in genomic lung or PASMC DNA, we found the methylation status of the SOD3 promoter was similar between FD and IPAH. Furthermore, treatment with 5-aza-2′-deoxycytidine did not increase PASMC SOD3 mRNA, suggesting DNA methylation was not responsible for PASMC SOD3 expression. Though total histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity, acetylated histones, and acetylated SP1 were similar between IPAH and FD, treatment with two selective class I HDAC inhibitors increased SOD3 only in IPAH PASMC. Class I HDAC3 siRNA also increased SOD3 expression. Trichostatin A, a pan-HDAC inhibitor, decreased proliferation in IPAH, but not in FD PASMC. These data indicate that histone deacetylation, specifically via class I HDAC3, decreases SOD3 expression in PASMC and HDAC inhibitors may protect IPAH in part by increasing PASMC SOD3 expression.

Structural similarity of ribosomes from E. coli and A. salina

1978 ◽  
Vol 36 (2) ◽  
pp. 242-243
Author(s):  
M. Boublik ◽  
R.M. Wydro ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Ribosomal Proteins ◽  
Direct Evidence ◽  
Structural Similarity ◽  
Carbon Support ◽  
Artemia Salina ◽  
Uranyl Acetate ◽  
Biological Assays ◽  
E Coli ◽  
And Function ◽  
Fine Carbon

Ribosomes are ribonucleoprotein particles necessary for processing the genetic information of mRNA into proteins. Analogy in composition and function of ribosomes from diverse species, established by biochemical and biological assays, implies their structural similarity. Direct evidence obtained by electron microscopy seems to be of increasing relevance in understanding the structure of ribosomes and the mechanism of their role in protein synthesis.The extent of the structural homology between prokaryotic and eukaryotic ribosomes has been studied on ribosomes of Escherichia coli (E.c.) and Artemia salina (A.s.). Despite the established differences in size and in the amount and proportion of ribosomal proteins and RNAs both types of ribosomes show an overall similarity. The monosomes (stained with 0.5% aqueous uranyl acetate and deposited on a fine carbon support) appear in the electron micrographs as round particles with a diameter of approximately 225Å for the 70S E.c. (Fig. 1) and 260Å for the 80S A.s. monosome (Fig. 2).

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Tran Khac Vu ◽  
Nguyen Thi Thanh ◽  
Nguyen Van Minh ◽  
Nguyen Huong Linh ◽  
Nguyen Thi Phương Thao ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Hydroxamic Acids ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Ic50 Value ◽  
Mcf 7

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer 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 vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

Development and Validation of High-Content Analysis for Screening HDAC6-Selective Inhibitors

2021 ◽  
pp. 247255522110024
Author(s):  
Yunhong Nong ◽  
Yanyan Hou ◽  
Yuting Pu ◽  
Si Li ◽  
Yan Lan
Keyword(s):  
Content Analysis ◽  
Adverse Effects ◽  
Hdac Inhibitors ◽  
Histone H3 ◽  
Class I ◽  
Cell Seeding ◽  
Clinical Evaluations ◽  
Structure Activity ◽  
High Content Analysis ◽  
Development And Validation

Throughout recent decades, histone deacetylase (HDAC) inhibitors have shown encouraging potential in cancer treatment, and several pan-HDAC inhibitors have been approved for treating malignant cancers. Numerous adverse effects of pan-HDAC inhibitors have been reported, however, during preclinical and clinical evaluations. To avoid undesirable responses, an increasing number of investigations are focusing on the development of isotype-selective HDAC inhibitors. In this study, we present an effective and quantitative cellular assay using high-content analysis (HCA) to determine compounds’ inhibition of the activity of HDAC6 and Class I HDAC isoforms, by detecting the acetylation of their corresponding substrates (i.e., α-tubulin and histone H3). Several conditions that are critical for HCA assays, such as cell seeding number, fixation and permeabilization reagent, and antibody dilution, have been fully validated in this study. We used selective HDAC6 inhibitors and inhibitors targeting different HDAC isoforms to optimize and validate the capability of the HCA assay. The results indicated that the HCA assay is a robust assay for quantifying compounds’ selectivity of HDAC6 and Class I HDAC isoforms in cells. Moreover, we screened a panel of compounds for HDAC6 selectivity using this HCA assay, which provided valuable information for the structure–activity relationship (SAR). In summary, our results suggest that the HCA assay is a powerful tool for screening selective HDAC6 inhibitors.

Organometallics in prostaglandin synthesis

1988 ◽  
Vol 326 (1592) ◽  
pp. 579-585 ◽  
Keyword(s):  
Conjugate Addition ◽  
Prostaglandin Synthesis ◽  
Side Chain ◽  
Prostaglandin E ◽  
Controlled Synthesis ◽  
One Pot ◽  
Naturally Occurring ◽  
Chain Unit ◽  
Alkyl Iodides

An extremely short way to prostaglandins has been opened by combining the newly devised organometallic methodologies. Convergent, one-pot creation of the prostanoid framework is achieved by organocopper conjugate addition of the S-configurated ω-side-chain unit to (R)-4-trialkylsiloxy-2-cyclopentenone followed by the organotin-aided trapping of the enolate intermediate by α-side-chain alkyl iodides. Prostaglandin E 2 can be prepared in only three steps from the chiral building units. The protected 5,6-didehydro-PGE 2 derivatives thus obtained serve as common intermediates for the synthesis of a variety of naturally occurring prostaglandins including prostacyclin. This approach is also useful for the controlled synthesis of isocarbacyclin.

Identification of 2-arylquinazolines with alkyl-polyamine motifs as potent antileishmanial agents: Synthesis and biological evaluation studies

2022 ◽  
Author(s):  
Anjila Kumari ◽  
Tara Jaiswal ◽  
Vinay Kumar ◽  
Neha Hura ◽  
Gulshan Kumar ◽  
...  
Keyword(s):  
Evaluation Studies ◽  
Biological Evaluation ◽  
Side Chain ◽  
Chain Ring ◽  
Synthesis And Biological Evaluation

2-Arylquinazolines with a range of alkyl polyamines as side chain/ring functional motifs at 4th-position were considered for antileishmanial study with the rationale that related heterocyclic scaffolds and the polyamine functionalities...

Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors

2016 ◽  
Vol 121 ◽  
pp. 592-609 ◽  
Author(s):  
Koichi Narita ◽  
Keisuke Matsuhara ◽  
Jun Itoh ◽  
Yui Akiyama ◽  
Singo Dan ◽  
...  
Keyword(s):  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Synthesis And Biological Evaluation
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