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 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 Design, Synthesis, and Antitumor Activity of a Series of Novel 4-(Aromatic Sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-ones

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5459
Author(s):  
Naiguo Xing ◽  
Chen Chen ◽  
Qiu Zhong ◽  
Shilong Zheng ◽  
Guangdi Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Lead Compound ◽  
Flow Cytometry Analysis ◽  
Anticancer Activities ◽  
Design Synthesis ◽  
Cascade Cyclization ◽  
Hela Cell Lines ◽  
M Phase ◽  
Ic50 Values ◽  
Metal Catalyzed

Many sulfonamides show anticancer activity. Based on benzenesulfonylazaspirodienone (HL-X9) identified in our previous work, we optimized the lead compound for better efficacy, thereby synthesizing a series of novel 4-(aromatic sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-one derivatives through a key step of metal-catalyzed cascade cyclization. The preliminary antiproliferative tests have shown that the anticancer activities of acetyl-protected mannose-linked sulfonylazaspirodienone derivatives (7i–7l) have been greatly improved. Among them, 7j is the most potent derivative, with IC50 values of 0.17 µM, 0.05 µM, and 0.07 µM for A549, MDA-MB-231, and HeLa cell lines, respectively. Flow cytometry analysis shows that 7j arrests MDA-MB-231 cells in the G2/M phase and has a certain effect on the apoptosis of MDA-MB-231 cells. In addition, the acute toxicity of 7j was lower than that of adriamycin.

scholarly journals Design, Synthesis and Biological Evaluation of Novel Coumarin-Based Hydroxamate Derivatives as Histone Deacetylase (Hdac) Inhibitors with Antitumor Activities

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2569 ◽  
Author(s):  
Feifei Yang ◽  
Na Zhao ◽  
Jiali Song ◽  
Kongkai Zhu ◽  
Cheng-shi Jiang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
A549 Cells ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Design Synthesis ◽  
M Phase ◽  
Ic50 Values

A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.

Design, synthesis, and preliminary bioactivity studies of substituted purine hydroxamic acid derivatives as novel histone deacetylase (HDAC) inhibitors

MedChemComm ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 1887-1891 ◽  
Author(s):  
Junhua Wang ◽  
Feng'e Sun ◽  
Leiqiang Han ◽  
Xuben Hou ◽  
Xiaole Pan ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Tumor Therapy ◽  
Hdac Inhibitors ◽  
Hydroxamic Acids ◽  
Hdac Inhibition ◽  
Design Synthesis ◽  
Hydroxamic Acid Derivatives

Histone deacetylase (HDAC) is a clinically validated target for anti-tumor therapy. In order to increase HDAC inhibition and efficiency, we developed a series of novel substituted purine hydroxamic acids as potent HDAC inhibitors.

scholarly journals Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition

2021 ◽  
Vol 57 (7) ◽  
pp. 867-870
Author(s):  
Claudio Cianferotti ◽  
Valentina Faltoni ◽  
Elena Cini ◽  
Elena Ermini ◽  
Francesca Migliorini ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hydroxamic Acids ◽  
Hdac Inhibition ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

The bioconjugation of hydroxamic acids to antibodies has been made possible through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure that releases hydroxamates in the cells.

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.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Synthesis, DFT Calculations, Antiproliferative, Bactericidal Activity and Molecular Docking of Novel Mixed-Ligand Salen/8-Hydroxyquinoline Metal Complexes

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4725
Author(s):  
Badriah Saad Al-Farhan ◽  
Maram T. Basha ◽  
Laila H. Abdel Rahman ◽  
Ahmed M. M. El-Saghier ◽  
Doaa Abou El-Ezz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Metal Complexes ◽  
Wide Spectrum ◽  
Mixed Ligand ◽  
Molecular Formula ◽  
Hep G2 ◽  
Anticancer Activities ◽  
Azomethine Group ◽  
Ic50 Values

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2′-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1H NMR, 13C NMR, UV–VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H2O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H2O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature.

Nonenzymatic Catalysis by Metal Ions and Phosphoric Acid Esters of Hydroxamic Acid Formation

1980 ◽  
Vol 35 (6) ◽  
pp. 727-730
Author(s):  
Oemer Saygin ◽  
Peter Decker
Keyword(s):  
Amino Acids ◽  
Phosphoric Acid ◽  
Metal Ions ◽  
Inorganic Phosphate ◽  
Hydroxamic Acid ◽  
Hydroxamic Acids ◽  
Bivalent Ions ◽  
No Release ◽  
Catalytic Effects ◽  
Acid Esters

Abstract Nonenzymatic catalysis by bivalent ions of Be, Mg, Ca, Zn, Mn, Ni and Co and bioorganic phosphates of the formation of hydroxamic acids from acetate or amino acids has been studied systematically. Increased yields of hydroxamate were observed at particular combinations of reactants. The most prominent increase (ca. 15-fold) was found with acetate and Ni++, and with a combination of ATP and Be++. Among others especially ribose-5-phosphate and glucose-5-phosphate enhanced yields in the presence of most metal ions. Since no release of inorganic phosphate was observed, this effect cannot be interpreted as an evidence for intermediate transhosphorylation reactions; it may also result from simple catalytic effects of metal sugar complexes.

scholarly journals Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 437
Author(s):  
Shu-Qin Qin ◽  
Lian-Chun Li ◽  
Jing-Ru Song ◽  
Hai-Yun Li ◽  
Dian-Peng Li
Keyword(s):  
Anticancer Agents ◽  
Human Cancer ◽  
A549 Cells ◽  
Anticancer Activities ◽  
Human Cancer Cell Lines ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Diphenyl Tetrazolium Bromide ◽  
Conjugated Compounds

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC50 values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC50 values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC50 value of 1.13 μM.

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