scholarly journals Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink

2016 ◽  
Vol 113 (6) ◽  
pp. 1630-1635 ◽  
Author(s):  
Maxwell Z. Wilson ◽  
Rurun Wang ◽  
Zemer Gitai ◽  
Mohammad R. Seyedsayamdost
Keyword(s):  
Broad Spectrum ◽  
Marine Bacteria ◽  
Anticancer Agents ◽  
Mode Of Action ◽  
Resistance Mechanism ◽  
Acid Resistance ◽  
Structural Features ◽  
Anticancer Activities ◽  
Tropodithietic Acid ◽  
Biochemical Analyses

While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal–bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA’s cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed.

Discovery of Anticancer Agents from 2-Pyrazoline-Based Compounds

2020 ◽  
Vol 27 ◽  
Author(s):  
Qing-Shan Li ◽  
Bang-Nian Shen ◽  
Zhen Zhang ◽  
Ban-Feng Ruan ◽  
Shuying Luo
Keyword(s):  
Broad Spectrum ◽  
Anticancer Agents ◽  
Present Review ◽  
Pyrazole Derivatives ◽  
Anticancer Activities ◽  
Structural Units ◽  
Pharmacological Activities ◽  
The Relationship

: As nitrogen-containing five-membered heterocyclic structural units, the substituted pyrazole derivatives have broad spectrum of pharmacological activities, especially 4,5-dihydro-1H-pyrazoles that also commonly known as 2-pyrazolines. Since 2010, considerable studies have been found that the 2-pyrazoline derivatives possess potent anticancer activities. In present review, it covers the pyrazoline derivatives reported by literatures from 2010 till date (2010-2019). This review aims to establish the relationship between the anticancer activities variation and different substituents introduced into 2-pyrazoline core, which could provide important pharmacophore clues for the discovery of new anticancer agents that containing 2-pyrazoline scaffold.

scholarly journals A Review: Medicinally Important Nitrogen Sulphur Containing Heterocycles

2020 ◽  
Vol 14 (1) ◽  
pp. 49-64
Author(s):  
Praveen K. Sharma ◽  
Andleeb Amin ◽  
M. Kumar
Keyword(s):  
Broad Spectrum ◽  
Mode Of Action ◽  
Mammalian Cells ◽  
Heterocyclic Compounds ◽  
Structural Features ◽  
Present Review ◽  
Pharmacological Activities ◽  
Sulfur Heterocycles ◽  
Biological And Pharmacological Activities

Nitrogen sulphur containing heterocycles have specific properties due to which they can be used as a potential material in a different type of industries such as medicinal/pharmaceutical, paint, packing and textile, required for various chemical, physical operations and their use as products. Especially dyes, paint, agrochemicals, medicine, etc. make them more significant. In present days, Nitrogen-Sulfur heterocycles are repeatedly attracting the interest of chemists due to their exceptional bioactive behavior. The present study is a review of the work carried out by a chemist in the discovery of new, effective, medicinally important heterocyclic compounds. The present review basically focused on nitrogen-sulfur heterocycles of potential therapeutic interest, especially with thiazole, thiazine, pyrimidine, morpholine and piperazine heterosystems, benzothiazines, pyrazole-benzothiazines, morpholine-benzothiazines, piperazine-benzothiazines and pyrimidine-benzothiazoles, mainly due to their unique structural features, which enable them to exhibit a number of biological and pharmacological activities. Due to a novel mode of action, a broad spectrum of activity, lesser toxicity towards mammalian cells, and suitable profiles towards humans have triggered the use of Nitrogen Sulphur containing heterocycles in designing and synthesizing their derivatives with better properties. The overall objective of the review is to discuss the importance of novel biodynamic structurally diverse heterocycles of potential therapeutic interest: pyrimidine, morpholine, piperazine, pyrozole, benothiazoles, pyrimidobenzothiazoles, 4H-1,4-benzothiazines, pyrazolyl-benzothiazines, morpholinyl-benzothiazines and piperazinylbenzothiazines in order to have access to important commercial molecules for the search of better future.

An insight into synthesis and anticancer potential of thiazole and 4- thiazolidinone containing motifs

2021 ◽  
Vol 25 ◽  
Author(s):  
Devidas S. Bhagat ◽  
Pooja A. Chawla ◽  
Wasudev B. Gurnule ◽  
Sampada K. Shejul ◽  
Gurvinder S. Bumbrah
Keyword(s):  
Broad Spectrum ◽  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Current Trend ◽  
Medical Science ◽  
Building Blocks ◽  
Biological Properties ◽  
Specific Protein ◽  
Mature Stage ◽  
Anticancer Activities

Abstract: Over the years, the branch of oncology has reached a mature stage and substantial development and advancement have been achieved in this dimension of medical science. The synthesis and isolation of numerous novel anticancer agents of natural and synthetic origins have been reported. Thiazole and 4-thiazolidinone containing heterocyclic compounds, having a broad spectrum of pharmaceutical activities, represents a significant class of medicinal chemistry. Thiazole and 4- thiazolidinone are five-membered unique heterocyclic motifs containing S and N atoms as an essential core scaffold and have commendable medicinal significance. Thiazoles and 4-thiazolidinones containing heterocyclic compounds are used as building blocks for the next generation of pharmaceuticals. Thiazole precursors have been frequently used due to their capabilities to bind to numerous cancer-specific protein targets. Suitably, thiazole motifs have a biological suit via inhibition of different signaling pathways involved in cancer causes. So, the scientific community has always tried to synthesize novel thiazole-based heterocycles by carrying out different replacements of functional groups or skeleton around thiazole moiety. Herein, we report the current trend of research and development in anticancer activities of thiazoles and 4-thiazolidinones containing scaffolds. In the current study, we have also highlighted some other significant biological properties of thiazole, novel protocols of synthesis for the synthesis of the new candidates, along with a significant broad spectrum of the anticancer activities of thiazole containing scaffolds. This study facilitates the development of novel thiazole and 4- thiazolidinone containing candidates with potent, efficient anticancer activity and less cytotoxic property.

scholarly journals Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines

2021 ◽  
Vol 2021 ◽  
pp. 1-27
Author(s):  
Ghada M. Safwat ◽  
Kamel M. A. Hassanin ◽  
Eman T. Mohammed ◽  
Essam Kh. Ahmed ◽  
Mahmoud R. Abdel Rheim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Docking ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Structural Features ◽  
Anticancer Activities ◽  
Cycle Arrest ◽  
Hybrid Molecules ◽  
Mcf 7

Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC50 of the two compounds (3b and 3g) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only 3b and 3g had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (3a-e and 3g) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress via increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the 3a, 3b, and 3g in HepG2 and 3b and 3g in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 ( R 2 = 0.531 ; P = 0.001 ) and MCF-7 ( R 2 = 0.219 ; P = 0.349 ) cell lines. The results of molecular docking analysis of 3a-g into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds 3a-g showed 2 violations from Lipinski’s rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds 3a-g than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations.

scholarly journals Advances of Benzimidazole Derivatives as Anticancer Agents: Bench to Bedside

2022 ◽  
Author(s):  
Kashif Haider ◽  
Mohammad Shahar Yar
Keyword(s):  
Cancer Research ◽  
Biological Activity ◽  
Anticancer Drugs ◽  
Broad Spectrum ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Structural Features ◽  
Clinical Development ◽  
Benzimidazole Derivatives ◽  
Antimitotic Agent

Benzimidazole is one of the privileged nitrogen-containing scaffolds known for its versatile diversified role in insecticides, pesticides, dyes, pigments and pharmaceuticals. Due to its electron-rich environment, structural features and binding potency of various therapeutic targets, benzimidazole derivatives exhibit a broad spectrum of biological activity that majorly includes antimicrobial, antifungal, analgesics, anti-diabetic and anticancer agents. Several benzimidazole scaffolds bearing drugs are clinically approved; they are used for various indications. For example, Bilastine, Lerisetron, Maribavir and Nocodazole are the most widely used benzimidazole-based marketed drugs available as an antihistamine, antiviral and antimitotic agent, respectively. Another example is the recently approved anticancer drug Binimetinib and Selumetinib, which are indicated for BRAF mutated melanoma and plexiform neurofibromas. Not only this, many benzimidazole-based anticancer drugs are in late phases of clinical development. Due to the vast therapeutic potential of benzimidazole scaffold in cancer research, medicinal chemists have gained a lot of attraction to explore it more and develop novel, highly effective and target-specific benzimidazole-based potential anticancer drugs.

scholarly journals Acetylenic Aquatic Anticancer Agents and Related Compounds

2006 ◽  
Vol 1 (9) ◽  
pp. 1934578X0600100 ◽  
Author(s):  
Valery M Dembitsky ◽  
Dmitri O Levitsky ◽  
Tatyana A Gloriozova ◽  
Vladimir V Poroikov
Keyword(s):  
Anticancer Agents ◽  
Biological Activities ◽  
Aquatic Organisms ◽  
Structural Features ◽  
Biologically Active ◽  
Terrestrial Plants ◽  
Anticancer Activities ◽  
Pharmaceutical Industries ◽  
New Applications

Although acetylenes are common as components of terrestrial plants, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from aquatic organisms: cyanobacteria, algae, fungi, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifouling, antifungal, pesticidal, phototoxic, HIV inhibitory, and immuno-suppressive properties. There is no doubt that they are of great interest, especially for the medicinal and/or pharmaceutical industries. This review presents structures and describes cytotoxic and anticancer activities of more than 230 acetylenic metabolites isolated from aquatic organisms. With the computer program PASS some additional biological activities are also predicted, which point toward possible new applications of these compounds. This review emphasizes the role of aquatic acetylenic compounds as an important source of leads for drug discovery.

Synthesis and Antibacterial / Anticancer Activities of Compounds Containing Pyrazole Ring Linked to Piperazines

2020 ◽  
Vol 16 (4) ◽  
pp. 419-431
Author(s):  
Kishore K. Valluri ◽  
Tejeswara R. Allaka ◽  
IV Kasi Viswanath ◽  
Nagaraju PVVS
Keyword(s):  
Cell Line ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Cancer Cell Line ◽  
Pyrazole Ring ◽  
Therapeutic Effects ◽  
Anticancer Activities ◽  
Human Colon Cancer ◽  
Parent Molecule ◽  
Wide Range

Background: Many pyrazole piperazine derivatives are known to exhibit a wide range, thus being attractive for the drug design and synthesis of interesting class of widely studied heterocyclic compounds. It is therefore necessary to devote continuing effort for the identification and development of New Chemical Entities (NCEs) as potential antibacterial and anticancer agents to address serious health problems. Methods: A series of new compounds containing pyrazole ring linked to a piperazine hydrochloride moiety were synthesized and screened for their antibacterial activity, cytotoxicity of novel scaffolds are described by variation in therapeutic effects of parent molecule. The structure variants were characterized by using a blend of spectroscopic 1H NMR, 13C NMR, IR, Mass and chromatographic techniques. Results: When tested for in vitro antibacterial and anticancer activities, several of these compounds showed good activities. The target compounds 9b, 9a and 9e exhibited a high degree of anticancer activity against human colon cancer cell line Caco-2 and human breast cancer cell line MDAMB231. Further, 9a, 9b, 9d, and 9h showed better activity towards four medically relevant organisms; Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella Species compared to CPF. In the present investigation, cheminfomatics tools Molinspiration, 2003 and MolSoft, 2007 for the prediction of insilico molecular properties and drug likeness for the target compounds 9a-h was evaluated and positive results were observed. Conclusion: Our study revealed that the molecular framework presented here could be a useful template for the identification of novel small molecules as promising antibacterial/ anticancer agents.

Recent Development of Sulfonyl or Sulfonamide Hybrids as Potential Anticancer Agents: A Key Review

2018 ◽  
Vol 18 (4) ◽  
pp. 488-505 ◽  
Author(s):  
K. P. Rakesh ◽  
Shi-Meng Wang ◽  
Jing Leng ◽  
L. Ravindar ◽  
Abdullah M. Asiri ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Anticancer Agents ◽  
Side Effect ◽  
Docking Studies ◽  
Multi Drug Resistance ◽  
Anticancer Activities ◽  
Pharmacological Activities ◽  
Synthetic Compounds ◽  
Structure Activity ◽  
Anticancer Drug Discovery

Cancer is the second leading cause of death worldwide. There is always a huge demand for novel anticancer drugs and diverse new natural or synthetic compounds are developed continuously by scientists. Presently, a large number of drugs in clinical practice have showed pervasive side effect and multidrug resistance. Sulfonyl or sulfonamide hybrids became one of the most attractive subjects due to their broad spectrum of pharmacological activities. Sulfonyl hybrids were broadly explored for their anticancer activities and it was found that they possess minimum side effect along with multi-drug resistance activity. This review describes the most recent applications of sulfonyl hybrid analogues in anticancer drug discovery and further discusses the mechanistic insights, structure-activity relationships and molecular docking studies for the potent derivatives.

scholarly journals Biofabricated Fatty Acids-Capped Silver Nanoparticles as Potential Antibacterial, Antifungal, Antibiofilm and Anticancer Agents

2021 ◽  
Vol 14 (2) ◽  
pp. 139
Author(s):  
Mohammad Azam Ansari ◽  
Sarah Mousa Maadi Asiri ◽  
Mohammad A. Alzohairy ◽  
Mohammad N. Alomary ◽  
Ahmad Almatroudi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Silver Nanoparticles ◽  
Anticancer Agents ◽  
Sem Analysis ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Anticancer Efficacy ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Dose Dependent

The current study demonstrates the synthesis of fatty acids (FAs) capped silver nanoparticles (AgNPs) using aqueous poly-herbal drug Liv52 extract (PLE) as a reducing, dispersing and stabilizing agent. The NPs were characterized by various techniques and used to investigate their potent antibacterial, antibiofilm, antifungal and anticancer activities. GC-MS analysis of PLE shows a total of 37 peaks for a variety of bio-actives compounds. Amongst them, n-hexadecanoic acid (21.95%), linoleic acid (20.45%), oleic acid (18.01%) and stearic acid (13.99%) were found predominately and most likely acted as reducing, stabilizing and encapsulation FAs in LIV-AgNPs formation. FTIR analysis of LIV-AgNPs shows some other functional bio-actives like proteins, sugars and alkenes in the soft PLE corona. The zone of inhibition was 10.0 ± 2.2–18.5 ± 1.0 mm, 10.5 ± 2.5–22.5 ± 1.5 mm and 13.7 ± 1.0–16.5 ± 1.2 against P. aeruginosa, S. aureus and C. albicans, respectively. LIV-AgNPs inhibit biofilm formation in a dose-dependent manner i.e., 54.4 ± 3.1%—10.12 ± 2.3% (S. aureus), 72.7 ± 2.2%–23.3 ± 5.2% (P. aeruginosa) and 85.4 ± 3.3%–25.6 ± 2.2% (C. albicans), and SEM analysis of treated planktonic cells and their biofilm biomass validated the fitness of LIV-AgNPs in future nanoantibiotics. In addition, as prepared FAs rich PLE capped AgNPs have also exhibited significant (p < 0.05 *) antiproliferative activity against cultured HCT-116 cells. Overall, this is a very first demonstration on employment of FAs rich PLE for the synthesis of highly dispersible, stable and uniform sized AgNPs and their antibacterial, antifungal, antibiofilm and anticancer efficacy.

scholarly journals Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

2021 ◽  
Vol 22 (3) ◽  
pp. 1496
Author(s):  
Domenico Loreto ◽  
Giarita Ferraro ◽  
Antonello Merlino
Keyword(s):  
Anticancer Agents ◽  
Structural Features ◽  
Side Chain ◽  
Side Chains ◽  
Valuable Insight ◽  
Experimental Conditions ◽  
Egg White Lysozyme ◽  
Potential Applications ◽  
Model Protein ◽  
Hen Egg White

The structures of the adducts formed upon reaction of the cytotoxic paddlewheel dirhodium complex [Rh2(μ-O2CCH3)4] with the model protein hen egg white lysozyme (HEWL) under different experimental conditions are reported. Results indicate that [Rh2(μ-O2CCH3)4] extensively reacts with HEWL:it in part breaks down, at variance with what happens in reactions with other proteins. A Rh center coordinates the side chains of Arg14 and His15. Dimeric Rh–Rh units with Rh–Rh distances between 2.3 and 2.5 Å are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh–Rh distance of 3.2–3.4 Å binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents.

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