scholarly journals Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

2021 ◽  
Vol 14 (12) ◽  
pp. 1319
Author(s):  
Nils Goehringer ◽  
Yayi Peng ◽  
Bianca Nitzsche ◽  
Hannah Biermann ◽  
Rohan Pradhan ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Histone Deacetylases ◽  
Parent Compound ◽  
Hdac Inhibitors ◽  
Drug Candidate ◽  
Anticancer Activities ◽  
Drug Candidates ◽  
Anticancer Properties ◽  
Ic50 Values ◽  
Potent Drug

The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate.

scholarly journals An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme

2007 ◽  
Vol 401 (3) ◽  
pp. 659-665 ◽  
Author(s):  
Kristin Moreth ◽  
Daniel Riester ◽  
Christian Hildmann ◽  
René Hempel ◽  
Dennis Wegener ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Esterase Activity ◽  
Histone Deacetylases ◽  
Biological Activities ◽  
Hdac Inhibitors ◽  
Porcine Liver ◽  
Drug Candidates ◽  
Core Histones ◽  
Ic50 Values

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of ϵ-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration.

scholarly journals Natural Products as Modulators of Sirtuins

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3287 ◽  
Author(s):  
Berin Karaman Mayack ◽  
Wolfgang Sippl ◽  
Fidele Ntie-Kang
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Class Iii ◽  
Drug Candidates ◽  
Starting Point ◽  
Recent Developments ◽  
Potent Drug

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

scholarly journals Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1295 ◽  
Author(s):  
Kazi Mustafa Mahmud ◽  
Mahruba Sultana Niloy ◽  
Md Salman Shakil ◽  
Md Asiful Islam
Keyword(s):  
Colorectal Cancer ◽  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Chemical Properties ◽  
Drug Efficacy ◽  
Anticancer Activities ◽  
Drug Candidates ◽  
Ru Nanoparticles ◽  
Ru Complexes ◽  
And Migration

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity and CRC cells’ resistance to Pt drugs has piqued interest in the search for alternative metal-based drugs. Ruthenium (Ru)-based compounds displayed promising anticancer activity due to their unique chemical properties. Ru-complexes are reported to exert their anticancer activities in CRC cells by regulating different cell signaling pathways that are either directly or indirectly associated with cell growth, division, proliferation, and migration. Additionally, some Ru-based drug candidates showed higher potency compared to commercially available Pt-based anticancer drugs in CRC cell line models. Meanwhile Ru nanoparticles coupled with photosensitizers or anticancer agents have also shown theranostic potential towards CRC. Ru-nanoformulations improve drug efficacy, targeted drug delivery, immune activation, and biocompatibility, and therefore may be capable of overcoming some of the existing chemotherapeutic limitations. Among the potential Ru-based compounds, only Ru (III)-based drug NKP-1339 has undergone phase-Ib clinical trials in CRC treatment.

scholarly journals The Aquaporin-3-Inhibiting Potential of Polyoxotungstates

2020 ◽  
Vol 21 (7) ◽  
pp. 2467 ◽  
Author(s):  
Catarina Pimpão ◽  
Inês V. da Silva ◽  
Andreia F. Mósca ◽  
Jacinta O. Pinho ◽  
Maria Manuela Gaspar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Growth ◽  
Anticancer Drugs ◽  
Inhibitory Concentration ◽  
Yeast Cells ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Aquaporin 3 ◽  
Anticancer Properties ◽  
First Time

Polyoxometalates (POMs) are of increasing interest due to their proven anticancer activities. Aquaporins (AQPs) were found to be overexpressed in tumors bringing particular attention to their inhibitors as anticancer drugs. Herein, we report for the first time the ability of polyoxotungstates (POTs), such as of Wells–Dawson P2W18, P2W12, and P2W15, and Preyssler P5W30 structures, to affect aquaporin-3 (AQP3) activity and impair melanoma cell migration. The tested POTs were revealed to inhibit AQP3 function with different effects, with P2W18, P2W12, and P5W30 being the most potent (50% inhibitory concentration (IC50) = 0.8, 2.8, and 3.2 µM), and P2W15 being the weakest (IC50 > 100 µM). The selectivity of P2W18 toward AQP3 was confirmed in yeast cells transformed with human aquaglyceroporins. The effect of P2W12 and P2W18 on melanoma cells that highly express AQP3 revealed an impairment of cell migration between 55% and 65% after 24 h, indicating that the anticancer properties of these compounds may in part be due to the blockage of AQP3-mediated permeability. Altogether, our data revealed that P2W18 strongly affects AQP3 activity and cancer cell growth, unveiling its potential as an anticancer drug against tumors where AQP3 is highly expressed.

TrizbenzIm, Cu-Trizbenzim and Zn-Trizbenzim as G-Quadruplex Inducing and Stabilizing Compounds on Human Telomeric Sequence and their Anticancer Properties

2021 ◽  
Vol 21 ◽  
Author(s):  
Renuga Duraisamy ◽  
Palanisamy U. Maheswari ◽  
Kadhar M.M. Sheriffa Begum ◽  
Dharmar Prabhakaran
Keyword(s):  
Telomeric Sequence ◽  
Thiazole Orange ◽  
Anticancer Activities ◽  
X Ray ◽  
Anticancer Properties ◽  
Telomere Sequence ◽  
G Quadruplex ◽  
Ic50 Values ◽  
Natural Amino Acids ◽  
Nanomolar Range

Background: The benzimidazole and their derivatives have rich biological relevance with respect to available natural amino acids and their role in protein folding and quaternary conformations. Thus the ligand trizbenzIm and their Cu(II) and Zn(II) metal complexes were prepared to induce G-quadruplex conformation even under no salt conditions with remarkable anticancer activities. Methods: The ligand N,N’,N’’-Tris-(1H-benzoimidazol-2-ylmethyl)-[1,3,5]triazine-2,4,6-triamine (trizbenzIm) and its Cu and Zn complexes (Cu-trizbenzIm, Zn-trizbenzIm) were synthesized and characterized by IR, NMR and MALDI-TOF techniques. The pure ligand and its complexes were interacted with human telomere DNA sequence d(TTAGGG), HTelo8and HTelo20and the interactions were followed by circular dichroism spectroscopy, FID assay and molecular docking techniques.The compounds were tested for anticancer activity towards selected cell lines. Results: All the three compounds stabilized the HTelo8 and HTelo20 in parallel and antiparallel G-quadruplex conformations with salt conditions. Under no salt conditions, the compounds induce and stabilize the G-quadruplex conformation in antiparallel topology, selectively. The pure ligand, Cu-trizbenzIm and Zn-trizbenzIm were involved in partial or classical intercalation together with some backbone interactions on the strand. The FID assay using thiazole orange intercalator clearly supports the proposed intercalation mode of binding for the three compounds, especially for the pure ligand and the Cu-complex. The MOE docking experiments using X-ray and NMR derived G-quadruplex models with the title compounds extensively support the G-quadruplex induction and stabilization of the telomere sequence by these compounds. The guanines bases involved in the G-tetrad formation interact well with the triazine and the benzimidazole part of the ligand through strong π-π interactions. The primary mode of binding is described as end stacking and intercalation of the compounds to the G-quadruplex structures. The Cu-trizbenzIm exhibited more anticancer property in comparison to the pure ligand and the Zn-trizbenzIm complex. The IC50 values were in the nanomolar range from 50 to 150nM in concentration. Conclusion: This novel self-induction of G-quadruplex is novel without the presence of any alkali metal ions.

scholarly journals Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

2019 ◽  
Vol 20 (2) ◽  
pp. 383 ◽  
Author(s):  
Florian Schmitt ◽  
Lisa Gosch ◽  
Alexandra Dittmer ◽  
Matthias Rothemund ◽  
Thomas Mueller ◽  
...  
Keyword(s):  
Hydroxamic Acid ◽  
Hydroxamic Acids ◽  
Microtubule Assembly ◽  
G1 Arrest ◽  
Hdac Inhibition ◽  
Anticancer Activities ◽  
Drug Candidates ◽  
M Phase ◽  
Ic50 Values ◽  
Varying Length

New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy.

scholarly journals Ellagic Acid and Schisandrins: Natural Biaryl Polyphenols with Therapeutic Potential to Overcome Multidrug Resistance in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 458
Author(s):  
Sabesan Yoganathan ◽  
Anushan Alagaratnam ◽  
Nikita Acharekar ◽  
Jing Kong
Keyword(s):  
Multidrug Resistance ◽  
Small Molecules ◽  
Anticancer Drugs ◽  
Abc Transporters ◽  
Ellagic Acid ◽  
Therapeutic Potential ◽  
Anticancer Activities ◽  
Glycoprotein P ◽  
Major Mechanism ◽  
Anticancer Properties

Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of ‘biaryl’ polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.

Synthesis and biological evaluation of thiophene-based hydroxamate derivatives as HDACis with antitumor activities

2020 ◽  
Vol 12 (8) ◽  
pp. 655-672 ◽  
Author(s):  
Feifei Yang ◽  
Lina Han ◽  
Na Zhao ◽  
Yang Yang ◽  
Di Ge ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Xenograft Model ◽  
Biological Evaluation ◽  
Anticancer Activities ◽  
Antitumor Activities ◽  
Cancer Treatments

Aim:   Histone deacetylases (HDACs) are one of the validated targets for cancer treatments. In our previous work, we designed a series of bis-substituted aromatic amide HDAC inhibitors (HDACis), among which compounds 7 and 8 showed promising anticancer effects. However, the low solubilities prevented their subsequent developments. We developed additional thiophene-based hydroxamate HDACis in order to improve their physicochemical properties. Materials & methods: In vitro biological evaluations of these analogs revealed potent antiproliferative and antimigrated activities. More importantly, compound 10h exhibited excellent in vivo antitumor activities in MDA-MB-231 xenograft model mice. Furthermore, 10h showed better anticancer activities and drug-like properties than 7. Results & conclusion: Our results proved that thiophene-based hydroxamate HDACis can serve as a promising framework for developing potential anticancer agents.

scholarly journals Valproic Acid Prodrug Affects Selective Markers, Augments Doxorubicin Anticancer Activity and Attenuates Its Toxicity in a Murine Model of Aggressive Breast Cancer

2021 ◽  
Vol 14 (12) ◽  
pp. 1244
Author(s):  
Nataly Tarasenko ◽  
Harel Josef Wilner ◽  
Abraham Nudelman ◽  
Gania Kessler-Icekson ◽  
Ada Rephaeli
Keyword(s):  
Breast Cancer ◽  
Valproic Acid ◽  
Tumor Growth ◽  
Murine Model ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Therapeutic Targets ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Dna Damage And Repair

We studied the unique inhibitor of the histone deacetylases (HDAC) valproate-valpromide of acyclovir (AN446) that upon metabolic degradation release the HDAC inhibitor (HDACI) valproic acid (VPA). Among the HDAC inhibitors that we have tested, only AN446, and to a lesser extent VPA, synergized with doxorubicin (Dox) anti-cancer activity. Romidepsin (Rom) was additive and the other HDACIs tested were antagonistic. These findings led us to test and compare the anticancer activities of AN446, VPA, and Rom with and without Dox in the 4T1 triple-negative breast cancer murine model. A dose of 4 mg/kg once a week of Dox had no significant effect on tumor growth. Rom was toxic, and when added to Dox the toxicity intensified. AN446, AN446 + Dox, and VPA + Dox suppressed tumor growth. AN446 and AN446 + Dox were the best inhibitory treatments for tumor fibrosis, which promotes tumor growth and metastasis. Dox increased fibrosis in the heart and kidneys, disrupting their function. AN446 most effectively suppressed Dox-induced fibrosis in these organs and protected their function. AN446 and AN446 + Dox treatments were the most effective inhibitors of metastasis to the lungs, as measured by the gap area. Genes that control and regulate tumor growth, DNA damage and repair, reactive oxygen production, and generation of inflammation were examined as potential therapeutic targets. AN446 affected their expression in a tissue-dependent manner, resulting in augmenting the anticancer effect of Dox while reducing its toxicity. The specific therapeutic targets that emerged from this study are discussed.

scholarly journals Factors governing the affinity and selectivity of histone deacetylase inhibitors for the HDAC8 enzyme active site: Implications for anticancer therapy

2020 ◽  
Author(s):  
Nikolay Toshev ◽  
Diana Cheshmedzhieva ◽  
Todor Dudev
Keyword(s):  
Cancer Progression ◽  
Histone Deacetylases ◽  
Density Functional ◽  
Rational Design ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Density Functional Theory Calculations ◽  
Post Translational Modifications ◽  
Enzyme Active Site ◽  
Anticancer Properties

Disruptions in post-translational modifications of chromatin structure promote uncontrollable cell growth branded as a hallmark of tumor lesions. The overexpression/hyperactivity of histone deacetylases (HDACs) is a common feature for the tumorogenesis and cancer progression. Several inhibitors of histone deacetylases (mainly hydroxamic acid derivatives) have been successfully used as drugs in fighting tumor formations. However, there is no systematic study on the factors controling the affinity and selectivity of this type of inhibitors to the host enzyme thus hampering successful rational design of more potent and selective anticancer drugs. Herein, in an attempt to illuminate the mechanism of the host – guest interactions in these systems at atomic level we systematically study the effect of various factors in the process and unravel its key determinants.  Density functional theory calculations have been employed. Our findings have the potential to be employed as guidelines in designing new HDAC inhibitors with improved anticancer properties.

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