scholarly journals Multivalent Carbonic Anhydrases Inhibitors

2019 ◽  
Vol 20 (21) ◽  
pp. 5352 ◽  
Author(s):  
Fabrizio Carta ◽  
Pascal Dumy ◽  
Claudiu T. Supuran ◽  
Jean-Yves Winum
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Diagnostic Tools ◽  
Biomolecular Recognition ◽  
Carbonic Anhydrases ◽  
Biological Targets ◽  
Processing Enzymes ◽  
Zinc Metalloenzymes ◽  
Antiglaucoma Agents ◽  
Isoform Selectivity

Biomolecular recognition using a multivalent strategy has been successfully applied, this last decade on several biological targets, especially carbohydrate-processing enzymes, proteases, and phosphorylases. This strategy is based on the fact that multivalent interactions of several inhibitory binding units grafted on a presentation platform may enhance the binding affinity and selectivity. The zinc metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are considered as drug targets for several pathologies, and different inhibitors found clinical applications as diuretics, antiglaucoma agents, anticonvulsants, and anticancer agents/diagnostic tools. Their main drawback is related to the lack of isoform selectivity leading to serious side effects for all pathologies in which they are employed. Thus, the multivalent approach may open new opportunities in the drug design of innovative isoform-selective carbonic anhydrase inhibitors with biomedical applications.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

scholarly journals Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action

2020 ◽  
Author(s):  
Nelson V. Simwela ◽  
Katie R. Hughes ◽  
Michael T. Rennie ◽  
Michael P. Barrett ◽  
Andrew P. Waters
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Reverse Genetics ◽  
Enzyme Inhibitors ◽  
Artemisinin Resistance ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Malaria Parasites

AbstractCurrent malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.Graphical abstract

scholarly journals Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds

2020 ◽  
Vol 21 (22) ◽  
pp. 8692
Author(s):  
Alessandra Benassi ◽  
Filippo Doria ◽  
Valentina Pirota
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Biological Properties ◽  
Aromatic Rings ◽  
Antitumor Effects ◽  
Comprehensive Overview ◽  
Biological Targets ◽  
Structural Modifications ◽  
Starting Point ◽  
Oxadiazole Derivatives

Nowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles—five-membered aromatic rings—emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially on 1,2,4 and 1,3,4 regioisomers. In the last years, an increasing number of oxadiazole derivatives, with remarkable cytotoxicity for several tumor lines, were identified. Structural modifications, that ensure higher cytotoxicity towards malignant cells, represent a solid starting point in the development of novel oxadiazole-based drugs. To increase the specificity of this strategy, outstanding oxadiazole scaffolds have been designed to selectively interact with biological targets, including enzymes, globular proteins, and nucleic acids, showing more promising antitumor effects. In the present work, we aim to provide a comprehensive overview of the anticancer activity of these heterocycles, describing their effect on different targets and highlighting how their structural versatility has been exploited to modulate their biological properties.

scholarly journals Synthetic small-molecule RNA ligands: future prospects as therapeutic agents

MedChemComm ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 1242-1255 ◽  
Author(s):  
A. Di Giorgio ◽  
M. Duca
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Therapeutic Agents ◽  
Future Prospects ◽  
Biologically Relevant ◽  
Biological Targets ◽  
Rna Ligands ◽  
Innovative Drugs ◽  
Synthetic Small Molecule

RNA is one of the most intriguing and promising biological targets for the discovery of innovative drugs in many pathologies and various biologically relevant RNAs that could serve as drug targets have already been identified.

scholarly journals Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII

2020 ◽  
Vol 21 (7) ◽  
pp. 2621
Author(s):  
Priya Hargunani ◽  
Nikhil Tadge ◽  
Mariangela Ceruso ◽  
Janis Leitans ◽  
Andris Kazaks ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Inhibitory Activity ◽  
Phenyl Ring ◽  
Drug Targets ◽  
Binding Mode ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Single Digit ◽  
Ca Ix ◽  
Shed Light

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

Cyanobacterial carbonic anhydrases

2005 ◽  
Vol 83 (7) ◽  
pp. 721-734 ◽  
Author(s):  
Anthony K-C So ◽  
George S Espie
Keyword(s):  
Carbonic Anhydrase ◽  
Gene Families ◽  
Marine Cyanobacteria ◽  
Carbonic Anhydrases ◽  
Catalytic Function ◽  
Concentrating Mechanism ◽  
Number Distribution ◽  
Zinc Metalloenzymes

Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible dehydration of HCO3–. These enzymes are encoded by at least five distinct, evolutionarily unrelated gene families, four of which have been found among the cyanobacteria examined to date. However, the distribution and expression of these cyanobacterial α-, β-, γ-, and ∈-CAs and their homologues among species have not yet been investigated in great detail. In this study, the number, distribution, and catalytic function of known and putative CAs and CA-like proteins from a variety of freshwater and marine cyanobacteria are examined.Key words: carbonic anhydrase, carboxysome, CO2-concentrating mechanism, cyanobacteria, Prochlorococcus, Synechococcus, Synechocystis.

scholarly journals Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Baki Vijaya Bhaskar ◽  
Aluru Rammohan ◽  
Tirumalasetty Munichandra Babu ◽  
Gui Yu Zheng ◽  
Weibin Chen ◽  
...  
Keyword(s):  
Binding Energy ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Binding Pocket ◽  
Pharmacophore Modeling ◽  
Boswellic Acid ◽  
Lead Compounds ◽  
Donor And Acceptor ◽  
In Silico Studies ◽  
Dietary Agents

AbstractDietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets

2017 ◽  
Vol 25 (5) ◽  
pp. 1543-1555 ◽  
Author(s):  
Alane B. Vermelho ◽  
Giseli R. Capaci ◽  
Igor A. Rodrigues ◽  
Verônica S. Cardoso ◽  
Ana Maria Mazotto ◽  
...  
Keyword(s):  
Drug Targets ◽  
Carbonic Anhydrases

Transcription Inhibition by Organometallic Ruthenium - Arene Anticancer Complexes in Live Mammalian Cells

2012 ◽  
Vol 65 (9) ◽  
pp. 1271 ◽  
Author(s):  
Astrid Astarina ◽  
Mun Juinn Chow ◽  
Wee Han Ang
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Transcription Inhibition ◽  
Biological Targets ◽  
Arene Ligands ◽  
Arene Ligand ◽  
Anticancer Complexes ◽  
Covalent Adducts ◽  
The Spectator ◽  
Ruthenium Arene

Organometallic ruthenium–arene RAPTA complexes, currently being actively pursued as potential anticancer agents, interact with intracellular biological targets to form covalent adducts. Because their mode of action is still unclear, we investigated their binding with DNA and the ability of ruthenated-DNA adducts to elicit cellular responses such as transcription inhibition and repair. To investigate the influence of the spectator arene ligands on RAPTA activity, a novel RAPTA complex containing the bulky 1,3,5-triisopropylbenzene ligand was synthesized and characterized. Transcription experiments carried out in live mammalian cells using ruthenated plasmid probes revealed that increasing steric bulk of the arene ligand did not improve its ability to arrest transcription.

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