scholarly journals Anticancer activity of new molecular hybrids combining 1,4-naphthalenedione motif with phosphonic acid moiety in hepatocellular carcinoma HepG2 cells.

1970 ◽  
Vol 64 (1) ◽  
Author(s):  
Angelika Długosz ◽  
Katarzyna Gach ◽  
Jacek Szymański ◽  
Jakub Modranka ◽  
Tomasz Janecki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Phosphonic Acid ◽  
Anticancer Agents ◽  
Hepg2 Cells ◽  
Acid Moiety ◽  
Drug Candidates ◽  
Hybrid Molecules ◽  
Ic50 Values ◽  
Apoptosis Inducer ◽  
Molecular Hybrids

Structural motifs found in naturally occurring compounds are frequently used by researchers to develop novel synthetic drug candidates. Some of these new agents are hybrid molecules which are designed through a concept of combining more than one functional element. In this report, anticancer activity of new synthetic molecular hybrids, substituted 3-diethoxyphosphorylnaphtho[2,3-b]furan-4,9-diones and 3-diethoxyphosphorylbenzo[f]indole-4,9-diones, which integrate natural 1,4-naphtalenedione scaffold, present in several anticancer agents, with pharmacophoric phosphonate moiety, were tested against hepatocellular cell line HepG2. Cytotoxicity was examined using MTT assay. Two most potent compounds, furandione 8a and benzoindoldione 12a, which reduced the number of viable HepG2 cells with the IC50 values of 4.13 µM and 5.9 µM, respectively, were selected for further research. These compounds decreased the mRNA expression levels of several genes: Bcl-2, angiogenic vascular endothelial growth factor (VEGF), c-Fos, caspase-8 and increased the expression of Bax, caspase-3 and -9, c-Jun, p21, p53, as determined by quantitative real-time PCR. The ability of these compounds to induce apoptosis and DNA damage was studied by flow cytometry. The obtained data showed that the new compounds inhibited cell viability by increasing apoptosis and decreasing angiogenesis. Compound 8a was a much stronger apoptosis inducer as compared with 12a and strongly activated the intrinsic pathway of apoptosis, associated with the loss of mitochondrial membrane potential and changes in Bax/Bcl-2 ratio. These findings show that the synthetic hybrids combining 1,4-naphthalenedione system and phosphonic acid moiety display potential to be further explored in the development of new anticancer agents.

Development and Advances of Drugs for Cancer Theranostics – PART-IV

2021 ◽  
Vol 21 (18) ◽  
pp. 1644-1644
Author(s):  
Lian-Shun Feng
Keyword(s):  
Drug Discovery ◽  
Side Effects ◽  
Anticancer Activity ◽  
Anticancer Drug ◽  
Anticancer Agents ◽  
Drug Repurposing ◽  
Biological Properties ◽  
Drug Candidates ◽  
Pharmacokinetic Profiles ◽  
Hybrid Molecules

Cancer, a highly heterogeneous disease at intra/inter patient levels, is one of the most serious threats to human health across the world [1, 2]. Notwithstanding the noteworthy advances in its treat-ment, the morbidity and mortality of cancer are projected to grow for a long period, and the global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020 [3]. Accordingly, there is a constant need to explore novel anticancer agents. <p> There are several strategies to discover novel anticancer candidates: (1) new lead hits or candidates from natural resources [4] whichexhibit various biological properties and are a rich source of com-pounds in drug discovery due to the structural and mechanistic diversity, and more than 60% anti-cancer agents can be traced to a natural product; (2) Molecular hybridization is one of the most prom-ising strategies for the discovery of novel anticancer drug candidates since hybrid molecules have the potential to bind multiple targets or to enhance the effect through acting with another bio-target or to counterbalance the side effects caused by the other part of the hybrid [5]; (3) Dimerization is a useful tool to develop novel anticancer drug candidates with enhanced biological activity, reduced side effects and improved pharmacokinetic profiles [6]; (4) Drug repurposing strategy is is an attractive strategy and has been approved, along with non-anticancer macrolide drugs for the treatment of cancer, for anticancer drug discovery since toxicity and pharmacokinetic profiles have already been estab-lished [7]. <p> Heterocycles coumarin, β-lactone, macrolide and triazole are useful anticancer pharmacophores since their derivatives could exert the anticancer activity through diverse mechanisms, inclusive of inhibition of aromatase, carbonic anhydrase, ki-nase, P-glycoprotein, sulfatase, telomerase, vascular endothelial growth factor receptor 2 and tubulin [8-11]. In particular, nat-ural-derived coumarin, β-lactone and macrolide derivatives are important sources of new anticancer lead hits/candidates; mac-rolide repurposed drugs can circumvent high cost and long-time associated with traditional drug discovery strategies; couma-rin, β-lactone and macrolide hybrids as well as bis-triazole compounds have the potential to enhance the anticancer activity, overcome drug resistance, reduce the side effects and improve pharmacokinetic profiles.

Arylhydrazono/Aryldiazenyl Pyrazoles: Green One-Pot Solvent-Free Synthesis and Anticancer Evaluation

2020 ◽  
Vol 17 (10) ◽  
pp. 772-778
Author(s):  
Abdulrhman Alsayari ◽  
Abdullatif Bin Muhsinah ◽  
Yahya I. Asiri ◽  
Jaber Abdullah Alshehri ◽  
Yahia N. Mabkhot ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Binding Mode ◽  
Docking Studies ◽  
Solvent Free ◽  
Pyrazole Derivatives ◽  
One Pot ◽  
Solvent Free Conditions ◽  
Hybrid Molecules

The aim of this study was to synthesize and evaluate the biological activity of pyrazole derivatives, in particular, to perform a “greener” one-pot synthesis using a solvent-free method as an alternative strategy for synthesizing hydrazono/diazenyl-pyridine-pyrazole hybrid molecules with potential anticancer activity. Effective treatment for all types of cancers is still a long way in the future due to the severe adverse drug reactions and drug resistance associated with current drugs. Therefore, there is a pressing need to develop safer and more effective anticancer agents. In this context, some hybrid analogues containing the bioactive pharmacophores viz. pyrazole, pyridine, and diazo scaffolds were synthesized by one-pot method. Herein, we describe the expedient synthesis of pyrazoles by a onepot three-component condensation of ethyl acetoacetate/acetylacetone, isoniazid, and arenediazonium salts under solvent-free conditions, and the evaluation of their cytotoxicity using a sulforhodamine B assay on three cancer cell lines. Molecular docking studies employing tyrosine kinase were also carried out to evaluate the binding mode of the pyrazole derivatives under study. 1-(4-Pyridinylcarbonyl)-3- methyl-4-(2-arylhydrazono)-2-pyrazolin-5-ones and [4-(2-aryldiazenyl)-3,5-dimethyl-1H-pyrazol-1- yl]-4-pyridinylmethanones, previously described, were prepared using an improved procedure. Among these ten products, 1-isonicotinoyl-3-methyl-4-[2-(4-nitrophenyl)hydrazono]-2-pyrazolin-5-one (1f) displayed promising anticancer activity against the MCF-7, HepG2 and HCT-116 cell lines, with an IC50 value in the range of 0.2-3.4 μM. In summary, our findings suggest that pyrazoles containing hydrazono/ diazenyl and pyridine pharmacophores constitute promising scaffolds for the development of new anticancer agents.

scholarly journals Hybrid cis-stilbene Molecules: Novel Anticancer Agents

2019 ◽  
Vol 20 (6) ◽  
pp. 1300 ◽  
Author(s):  
Natalia Piekuś-Słomka ◽  
Renata Mikstacka ◽  
Joanna Ronowicz ◽  
Stanisław Sobiak
Keyword(s):  
Anticancer Agents ◽  
Biological Activities ◽  
Distinct Group ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Structure Activity ◽  
Polymerization Inhibitor ◽  
Hybrid Molecules ◽  
Tubulin Polymerization Inhibitor ◽  
Pharmacologically Active

The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design, synthesis and bioevaluation. Many novel multi-target-directed drug candidates were synthesized, and their biological activities were evaluated. For the design of anticancer hybrid compounds, the molecules of stilbenes, aromatic quinones, and heterocycles (benzimidazole, imidazole, pyrimidine, pyridine, pyrazole, quinoline, quinazoline) were applied. A distinct group of hybrids comprises the molecules built with natural compounds: Resveratrol, curcumin, coumarin, and oleanolic acid. In this review, we present the studies on bioactive hybrid molecules of a well-known tubulin polymerization inhibitor, combretastatin A-4 and its analogs with other pharmacologically active entities. The mechanism of anticancer activity of selected hybrids is discussed considering the structure-activity relationship.

New Uracil Analogs with Exocyclic Methylidene Group as Potential Anticancer Agents

2020 ◽  
Vol 20 (3) ◽  
pp. 359-368 ◽  
Author(s):  
Angelika Długosz-Pokorska ◽  
Joanna Drogosz ◽  
Marlena Pięta ◽  
Tomasz Janecki ◽  
Urszula Krajewska ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Elisa Test ◽  
Pcr Analysis ◽  
Cytotoxic Activities ◽  
Drug Candidates ◽  
Hybrid Molecules ◽  
M Phase

Background: Hybrid molecules combining uracil skeleton with methylidene exo-cyclic group were designed in the search for novel anticancer drug candidates. Objective: Two series of racemic 5-methylidenedihydrouracils, either 1,3-disubstituted or 1,3,6-trisubstituted were synthesized and tested for their possible cytotoxic activity against two cancer cell lines (HL-60 and MCF-7) and two healthy cell lines (HUVEC and MCF-10A). The most cytotoxic analogs were re-synthesized as pure enantiomers. The analog designated as U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], which had a very low IC50 value in HL-60 cell line (0.77μM) and was the most selective towards cancer cells was chosen for further experiments on HL-60 cell line, in order to determine the possible mechanism involved in its antineoplastic action. Methods: Cytotoxic activities of compound was assessed by the MTT assay. In order to explore the mechanism of U-332 activity, we performed quantitative real-time PCR analysis of p53 and p21 genes. Apoptosis, cell proliferation and DNA damage in HL-60 cells were determined using the flow cytometry. The ability of U-332 to determine GADD45ɑ protein level in HL-60 cells incubated with U-332 was analyzed by ELISA test. Results: U-332 was shown to generate excessive DNA damage (70% of the cell population), leading to p53 activation, resulting in p21 down-regulation and a significant increase of GADD45α protein, responsible for the cell cycle arrest in G2/M phase. Conclusion: U-332 can be used as a potential lead compound in the further development of novel uracil analogs as anticancer agents.

Current scenario of acridine hybrids with anticancer potential

2021 ◽  
Vol 21 ◽  
Author(s):  
Qihong Zhang ◽  
Xia Yu
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Rational Design ◽  
Complex Disease ◽  
Single Agent ◽  
Drug Candidates ◽  
Cycle Arrest ◽  
Current Scenario ◽  
Potential Activity ◽  
Almost All

: Cancer, a complex disease which involves abnormalities of multiple cellular pathways, is one of the most serious threatens to human health across the world. Chemotherapy with a single agent or a combined regimen is a standardized strategy for the treatment of almost all human cancers, and the cure rate of cancer increases with the continuous discovery of anticancer agents and the optimization of chemotherapy options. However, drug resistance especially multidrug resistance remains an obstacle in the effective treatment of cancer. Hence, it is urgent to develop novel agents with potential activity against cancers, especially drug-resistant forms. Acridine, which bears three fused rings, could intercalate into DNA and interfere with metabolic processes. Recently, acridines have been found with anticancer activity in a variety of malignancies through suppressing cell proliferation, stimulating apoptosis, and inducing cell cycle arrest, retarding migration, invasion and metastasis. Thus, acridines are useful scaffolds for the discovery of novel drug candidates with potent anticancer activity. This review focused on the current scenario of acridine hybrids with potential activity against cancers reported from Jan. 2015 to Feb. 2021. The mechanisms of action, the criteria of compound design as well as structure-activity relationships were also summarized to pave the way for further rational design of novel anticancer agents.

scholarly journals Microwave-Assisted Synthesis of Novel Bis-Flavone Dimers as New Anticancer Agents

2018 ◽  
Vol 16 (1) ◽  
pp. 66-75 ◽  
Author(s):  
Andrew McGown ◽  
Abby Ragazzon-Smith ◽  
John A. Hadfield ◽  
Herman Potgetier ◽  
Patricia A. Ragazzon
Keyword(s):  
Anticancer Activity ◽  
Click Chemistry ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Triazole Ring ◽  
Microwave Assisted Synthesis ◽  
Anticancer Properties ◽  
Microwave Assisted ◽  
Ic50 Values ◽  
High Yields

In this study, we describe a microwave-based click chemistry method used to prepare a family of novel bis-flavone dimers. The substituted 7-hydroxy and 4’-hydroxy flavonoids were linked through a triazole ring. The compounds were easily synthesized and purified in high yields. The bisflavonoids were tested on different cell lines including HCT116, HepG2, MCF7 and MOLT-4. Several analogues showed to have anticancer activity with IC50 values in the range of 20-60 μM. Flavonoids are known for their anticancer properties and this method provides the basis for new medicinal structures.

scholarly journals Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5235
Author(s):  
Katharigatta N. Venugopala ◽  
Mohammed Habeebuddin ◽  
Bandar E. Aldhubiab ◽  
Afzal Haq Asif
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Structural Features ◽  
Synthetic Methods ◽  
Potential Candidate ◽  
Human Cancer Cell Lines ◽  
Hybrid Molecules

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.

Design, Synthesis and Evaluation of Hybrid 2-Heteroaryl BenzimidazoleChalcone Derivatives as Anticancer Agents

2020 ◽  
Vol 17 ◽  
Author(s):  
Gajula Shyam Kumar ◽  
Bethi Rathnakar ◽  
Sridhar Gattu ◽  
Surender Singh Jadav ◽  
Nimma Rameshwar ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Phenyl Ring ◽  
Human Breast ◽  
Design Synthesis ◽  
Abl Tyrosine Kinase ◽  
Ovarian Cancer Cell Lines ◽  
Methoxy Groups ◽  
Ic50 Values ◽  
Human Breast Carcinoma Cells

: A series of 2-heteroaryl benzimidazole-chalcone hybrids were synthesized and the anticancer activity was estimated by MTT assay in human breast, lung, colon, and ovarian cancer cell lines. The biological results indicate that the compounds showed good anticancer activity with a range of IC50 values 0.056-19.5 µM. Compound 11b with hexa methoxy groups, bearing three methoxy groups on each terminal aryl ring exhibited a significant IC50 value (56 nM) against human breast carcinoma cells, which is 37 times higher potency in comparison with the reference Etoposide. Further compounds substituted variably with methoxy and nitro groups on the phenyl ring of chalcone showed more promising anticancer activity than the compounds with unsubstituted phenyl ring or variably alkyl-substituted phenyl ring of chalcone. The molecular docking results indicate that the synthesized compounds bind in the active site of Abl tyrosine kinase, the target of anticancer drug Imatinib. The present study provides the synergistic effect of hybrids, benzimidazole-chalcones as potential anticancer agents and will aid in the discovery of new anticancer agents.

scholarly journals EVALUATION OF IN VITRO CYTOTOXIC AND ANTICANCER ACTIVITY OF HEPATOPROTECTIVE POLYHERBAL FORMULATION IN CELL LINE MODEL

2019 ◽  
pp. 320-325
Author(s):  
JAYACHANDRA KUNCHA ◽  
THIRUGNANASAMBANTHAM P ◽  
KUMARAN S ◽  
NARAYANAN N ◽  
SHARMILA DEVI V
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Kidney Cell ◽  
Normal Liver ◽  
Cancer Cell Lines ◽  
Polyherbal Formulation ◽  
Ic50 Values

Introduction: The use of natural products as anticancer agents has a long history that began with folklore medicine and through the years has been incorporated into traditional and allopathic medicine. Several drugs currently used are derived from medicinal plants. Objective: The main objective of this study is to investigate the cytotoxic potential of hepatoprotective polyherbal formulation in normal and cancer cell lines. Methods: A 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was utilized to screen the cytotoxic activity. Results: The results revealed that the formulation does not induce much mortality in normal liver and kidney cell lines, and LC50 value of liver cell lines was found 1716.355 μg/ml and kidney cell lines 2464.910 μg/ml. The in vitro anticancer activity was performed on liver, colon, and prostate cancer cell lines, and IC50 values are found 2.077, 3.850, and 11.989 μg/ml, respectively, which show excellent anticancer activity. Conclusion: Based on the results obtained, the hepatoprotective polyherbal formulation is safe for normal cells and cytotoxic for cancer cells. Further, identification and quantification of phytoconstituents responsible for the activity are in progress.

scholarly journals Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents

2020 ◽  
Vol 13 (12) ◽  
pp. 471
Author(s):  
Valentin Studer ◽  
Nicoleta Anghel ◽  
Oksana Desiatkina ◽  
Timo Felder ◽  
Ghalia Boubaker ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkyl Aryl ◽  
Antiparasitic Activity ◽  
Human Foreskin Fibroblasts ◽  
Adenocarcinoma Cells ◽  
Human Lung Adenocarcinoma Cells ◽  
Ic50 Values ◽  
Dinuclear Ruthenium

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6–10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11–14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

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