Synthesis and antitumor properties of some new N-(5-R-benzyl-1,3-thiazol-2-yl)-4,5-dihydro-1H-imidazole-2-carboxamides

Background: Dihydrofolate reductase (DHFR) has been known for decades as a molecular target for antibacterial, antifungal and anti-malarial treatments. This enzyme is becoming increasingly important in the design of new anticancer drugs, which is confirmed by numerous studies including modelling, synthesis and in vitro biological research. This review aims to present and discuss some remarkable recent advances on the research of new DHFR inhibitors with potential anticancer activity. Methods: The scientific literature of the last decade on the different types of DHFR inhibitors has been searched. The studies on design, synthesis and investigation structure-activity relationship were summarized and divided into several subsections depending on the leading molecule and its structural modification. Various methods of synthesis, potential anticancer activity and possible practical applications as DHFR inhibitors of new chemical compounds were described and discussed. <p> Results: This review presents the current state of knowledge on the modification of known DHFR inhibitors and the structures and searching for over eighty new molecules, designed as potential anticancer drugs. In addition, DHFR inhibitors acting on thymidylate synthase (TS), carbon anhydrase (CA) and even DNA-binding are presented in this paper. <p> Conclusion: Thorough physicochemical characterization and biological investigations it is possible to understand structure-activity relationship of DHFR inhibitors. This will enable even better design and synthesis of active compounds, which would have the expected mechanism of action and the desired activity.

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Synthesis, Characterization, Anti-proliferative Evaluation, and DNA Flow Cytometry Analysis of Some 2-Thiohydantoin Derivatives

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200611093510 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1929-1941

Author(s):

Heba A. Elhady ◽

Hossa F. Al-Shareef

Keyword(s):

Anticancer Activity ◽

Schiff Bases ◽

Anticancer Agents ◽

Proliferative Activity ◽

Cancer Cell Line ◽

Aromatic Aldehydes ◽

Pharmaceutical Chemistry ◽

Dna Flow Cytometry ◽

Quinazoline Derivative ◽

Reference Drug

Background and Objective: Due to the well-documented anti-proliferative activity of 2-thiohydantoin incorporated with pyrazole, oxadiazole, quinazoline, urea, β-naphthyl carbamate and Schiff bases, they are noteworthy in pharmaceutical chemistry. Methods: An efficient approach for the synthesis of a novel series of 2-thiohydantoin derivatives incorporated with pyrazole and oxadiazole has proceeded via the reaction of the acyl hydrazide with chalcones and/or triethyl orthoformate. Schiff bases were synthesized by the reaction of the acyl hydrazide with different aromatic aldehydes. Moreover, Curtius rearrangement was applied to the acyl azide to obtain the urea derivative, quinazoline derivative, and carbamate derivative. Results: The synthesized compounds structures were discussed and confirmed depending on their spectral data. The anticancer activity of these heterocyclic compounds was evaluated against the breast cancer cell line (MCF-7), where they showed variable activity. Compound 5d found to have a superior anticancer activity, where it has (IC50 = 2.07 ± 0.13 μg/mL) in comparison with the reference drug doxorubicin that has (IC50 = 2.79 ± 0.07 μg / mL). Then compound 5d subjected to further studies such as cell cycle analysis and apoptosis. Apoptosis was confirmed by the upregulation of Bax, downregulation of Bcl-2, and the increase of the caspase 3/7percentage. Conclusion: Insertion of pyrazole, oxadiazole and, quinazoline moieties with 2-thiohydantoin moiety led to the enhancement of its anti-proliferative activity. Hence they can be used as anticancer agents.

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

Letters in Organic Chemistry ◽

10.2174/1570178617666200320104923 ◽

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.

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Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies

Current Bioactive Compounds ◽

10.2174/1573407213666170828165512 ◽

2019 ◽

Vol 15 (2) ◽

pp. 257-267 ◽

Cited By ~ 3

Author(s):

Paritosh Shukla ◽

Ashok Sharma ◽

Leena Fageria ◽

Rajdeep Chowdhury

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

In Silico ◽

Antimicrobial Agents ◽

Docking Studies ◽

Bioactive Molecules ◽

Microwave Assisted Synthesis ◽

Binding Affinities ◽

In Silico Docking

Background: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.

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Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200131120618 ◽

2020 ◽

Vol 15 (1) ◽

pp. 2-13 ◽

Cited By ~ 3

Author(s):

Hongyu Tao ◽

Ling Zuo ◽

Huanli Xu ◽

Cong Li ◽

Gan Qiao ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cdk Inhibitors ◽

Comprehensive Overview ◽

P53 Expression ◽

Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

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Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽

10.3390/cancers13081790 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1790

Author(s):

Katarzyna Malarz ◽

Jacek Mularski ◽

Michał Kuczak ◽

Anna Mrozek-Wilczkiewicz ◽

Robert Musiol

Keyword(s):

Cell Cycle ◽

Anticancer Activity ◽

Cell Cycle Arrest ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

P53 Protein ◽

Structural Similarity ◽

M Cell ◽

Cycle Arrest ◽

Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

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NBM-HD-1: A Novel Histone Deacetylase Inhibitor with Anticancer Activity

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/781417 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Wei-Jan Huang ◽

Yu-Chih Liang ◽

Shuang-En Chuang ◽

Li-Ling Chi ◽

Chi-Yun Lee ◽

...

Keyword(s):

Anticancer Activity ◽

Cancer Cells ◽

Anticancer Agents ◽

Xenograft Model ◽

Cyclin B1 ◽

Dependent Manner ◽

Cell Cycle Regulators ◽

Anticancer Activities ◽

Gene Expressions

HDAC inhibitors (HDACis) have been developed as promising anticancer agents in recent years. In this study, we synthesized and characterized a novel HDACi, termed NBM-HD-1. This agent was derived from the semisynthesis of propolin G, isolated from Taiwanese green propolis (TGP), and was shown to be a potent suppressor of tumor cell growth in human breast cancer cells (MCF-7 and MDA-MB-231) and rat glioma cells (C6), with an IC50ranging from 8.5 to 10.3 μM. Western blot demonstrated that levels of p21(Waf1/Cip1), gelsolin, Ac-histone 4, and Ac-tubulin markedly increased after treatment of cancer cells with NBM-HD-1. After NBM-HD-1 treatment for 1–4 h, p-PTEN and p-AKT levels were markedly decreased. Furthermore, we also found the anticancer activities of NBM-HD-1 in regulating cell cycle regulators. Treatment with NBM-HD-1,p21(Waf1/Cip1)gene expression had markedly increased whilecyclin B1andD1gene expressions had markedly decreased. On the other hand, we found that NBM-HD-1 increased the expressions of tumor-suppressor genep53in a dose-dependent manner. Finally, we showed that NBM-HD-1 exhibited potent antitumor activity in a xenograft model. In conclusion, this study demonstrated that this compound, NBM-HD-1, is a novel and potent HDACi with anticancer activityin vitroandin vivo.

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DESIGN AND ANTICANCER ACTIVITY PREDICTION OF DIHYROPYRIMIDINONE BASED NOVEL INHIBITORS OF P53-MDM2 INTERACTION

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10s4.21346 ◽

2017 ◽

Vol 10 (16) ◽

pp. 110

Author(s):

Surendra Kumar Nayak ◽

Gopal Lal Khatik ◽

Rakesh Narang ◽

Harish Kumar Chopra

Keyword(s):

Anticancer Activity ◽

Binding Affinity ◽

Anticancer Agents ◽

P53 Protein ◽

Docking Study ◽

Molecular Docking Study ◽

Activity Prediction ◽

Cycle Regulation ◽

Mdm2 Inhibitor ◽

Better Than

Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using “Cancer IN” server.Methods: In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC50, anticancer activity, and toxicity profile were designed. Lead L11 was obtained after sequential isosteric replacement of functional groups for optimization in compound L0.Results: The docking scores of L3-L11 found to be in range of 21-25 close to docking score 25 of SAR405838 and better than nutlin-3a. MDM2 binding affinity values (37-78 Kcal/mol) of all ligands were also found to better than that of nutlin-3a (37 Kcal/mol). Surprisingly, MDM2 binding affinity of L11 (78 Kcal/mol) found to be equal to that of SAR405838 and 2-fold greater than nutlin-3a.Conclusion: These data indicating that L11 as a potential lead from dihydropyrimidinones for inhibition of p53-MDM2 interaction.

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Synthesis of Novel 2-Thioxothiazolidin-4-one and Thiazolidine-2, 4-dione Derivatives as Potential Anticancer Agents

Natural Product Communications ◽

10.1177/1934578x1801300518 ◽

2018 ◽

Vol 13 (5) ◽

pp. 1934578X1801300

Author(s):

Alleni Suman Kumar ◽

Rathod Aravind Kumar ◽

Elala Pravardhan Reddy ◽

Vavilapalli Satyanarayana ◽

Jajula Kashanna ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Preliminary Data ◽

Cancer Cell Lines ◽

Structure Evolution ◽

Model Compounds ◽

Diverse Range ◽

Novel Method

A variety of novel thiazolidine derivatives (2-thioxothiazolidin-4-one and thiazolidine-2, 4-dione derivatives) have been prepared by using 2,4-diphenyl-2 H-chromene-3-carbaldehyde and its derivatives as starting materials. This is the first example of the preparation of thiazolidine derivatives through this novel method. Structure evolution of the resulting thiazolidine derivatives leads to anticancer agents. Our preliminary data for some model compounds on three cancer cell lines (MCF7, A549 and B-16) suggested reasonable anticancer activity against the A549 and B-16 cell lines, with IC50 values of 20.7 and 20.4 μM, respectively. This method is operationally simple and works with a diverse range of substrates.

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Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

Molecules ◽

10.3390/molecules26206305 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6305

Author(s):

Abdullah Mohammed Al-Majid ◽

M. Ali ◽

Mohammad Shahidul Islam ◽

Saeed Alshahrani ◽

Abdullah Saleh Alamary ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Stereoselective Synthesis ◽

Cancer Cell Lines ◽

Azomethine Ylides ◽

Active Member ◽

One Pot

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.

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