Design and Discovery of Novel Quinoxaline Derivatives as Dual DNA Intercalators and Topoisomerase II Inhibitors

2018 ◽  
Vol 18 (2) ◽  
pp. 195-209 ◽  
Author(s):  
Ibrahim H. Eissa ◽  
Abeer M. El-Naggar ◽  
Nour E.A. Abd El-Sattar ◽  
Ahmed S. A. Youssef
Keyword(s):  
Dna Binding ◽  
Cell Lines ◽  
Topoisomerase Ii ◽  
Docking Studies ◽  
Binding Affinities ◽  
Quinoxaline Derivatives ◽  
Inhibitory Activities ◽  
Cytotoxicity Activities ◽  
New Compounds

Backgroun/Methods: In attempt to develop new potent anti-tumor agents, a series of quinoxaline derivatives was designed and synthesized. The novel compounds were tested in vitro for their anti-proliferative activities against HePG-2, MCF-7 and HCT-116 cell lines. Additionally, DNA binding affinities as well as DNA-top II inhibitory activities of the synthesized compounds were investigated as potential mechanism for anticancer activity. Compounds 13, 15, 16 and 19 exhibited good cytotoxicity activities against the three cell lines (IC50 ranging from 7.6 to 32.4 µM) comparable to that of doxorubicin (IC50 = 9.8 µM). Results: Interestingly, the results of DNA binding and DNA-top II inhibition assays were in agreement with those of the cytotoxicity tests, where the most potent anticancer compounds showed good DNA binding affinities (IC50 ranging from 25.1 to 32.4 µM) and DNA-top II inhibitory activities (IC50 ranging from 6.4 to 15.3 µM) comparable to those of doxorubicin (IC50 = 28.1 and 3.8 μM, respectively). Furthermore, molecular docking studies were carried out for the new compounds in order to investigate their binding pattern with the prospective target, DNA-top II complex (PDB-code: 3qx3).

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

2019 ◽  
Vol 15 (2) ◽  
pp. 257-267 ◽  
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.

In Vitro Antitumor Evaluation of Some Hybrid Molecules Containing Coumarin and Quinolinone Moieties

2020 ◽  
Vol 19 (16) ◽  
pp. 2010-2018
Author(s):  
Youstina W. Rizzk ◽  
Ibrahim M. El-Deen ◽  
Faten Z. Mohammed ◽  
Moustafa S. Abdelhamid ◽  
Amgad I.M. Khedr
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Cancer Cell Lines ◽  
Bax Protein ◽  
Hybrid Molecules ◽  
Mcf 7

Background: Hybrid molecules furnished by merging two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery. Currently, coumarin hybrids have attracted the keen attention of researchers to discover their therapeutic capability against cancer. Objective: The present study aimed to evaluate the in vitro antitumor activity of a new series of hybrid molecules containing coumarin and quinolinone moieties 4 and 5 against four cancer cell lines. Materials and Methods: A new series of hybrid molecules containing coumarin and quinolinone moieties, 4a-c and 5a-c, were synthesized and screened for their cytotoxicity against prostate PC-3, breast MCF-7, colon HCT- 116 and liver HepG2 cancer cell lines as well as normal breast Hs-371 T. Results: All the synthesized compounds were assessed for their in vitro antiproliferative activity against four cancer cell lines and several compounds were found to be active. Further in vitro cell cycle study of compounds 4a and 5a revealed MCF-7 cells arrest at G2 /M phase of the cell cycle profile and induction apoptosis at pre-G1 phase. The apoptosis-inducing activity was evidenced by up-regulation of Bax protein together with the downregulation of the expression of Bcl-2 protein. The mechanism of cytotoxic activity of compounds 4a and 5a correlated to its topoisomerase II inhibitory activity. Conclusion: Hybrid molecules containing coumarin and quinolinone moieties represents a scaffold for further optimization to obtain promising anticancer agents.

Repositioning of Difluorinated Propanediones as Inhibitors of Histone Methyltransferases and their Biological Evaluation in Human Leukemic Cell Lines

2019 ◽  
Vol 18 (13) ◽  
pp. 1892-1899 ◽  
Author(s):  
Tanushree Pal ◽  
Asmita Sharda ◽  
Bharat Khade ◽  
C. Sinha Ramaa ◽  
Sanjay Gupta
Keyword(s):  
Cell Lines ◽  
Physiological Role ◽  
Leukemic Cell ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Leukemic Cell Lines ◽  
Histone Lysine ◽  
Histone Lysine Methyltransferase ◽  
Subsequent Decrease

Background: At present, ‘pharmaco-epigenomics’ constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy. Objective: Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated Propanediones (PR) as Histone lysine Methyltransferase inhibitors (HMTi). Methods: The cell lines of leukemic origin viz. histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT) were treated with PR-1 to 7 after docking studies with active pocket of HMT. The cell cycle analysis, in vitro methylation and cell proliferation assays were carried out to delineate their physiological role. Results: A small molecule PR-4, at 1 and 10µM, has shown to alter the methylation of histone H3 and H4 in both cell lines. Also, treatment shows an increase in G2/M population and a subsequent decrease in the G0/G1 population in U937. In JURKAT, an increase in both G2/M and S phase population was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the PR showed a cell growth of 42.6 and 53.4% comparable to adriamycin; 44.5 and 53.2% in U937 and JURKAT, respectively. The study suggests that PR-4 could emerge as a potential HMT inhibitor. Conclusion: The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be pro-apoptotic agents.

scholarly journals The Synthesis, Characterization, Cytotoxic Activity Assessment and Structure–Activity Relationship of 4-Aryl-6-(2,5-dichlorothiophen-3-yl)-2-methoxypyridine-3-carbonitriles

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4072
Author(s):  
Al-Refai ◽  
Ibrahim ◽  
Azmi ◽  
Osman ◽  
Bakar ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
In Vitro Cytotoxicity ◽  
Basic Medium ◽  
Condensation Process ◽  
Cytotoxicity Activities ◽  
Cytotoxicity Assessment ◽  
Relationship Of

A series of 2-methoxypyridine-3-carbonitrile (5a–i)-bearing aryl substituents were successfully synthesized in good yields by the condensation of chalcones (4a–i) with malononitrile in basic medium. The condensation process, in most cases, offers a route to a variety of methoxypyridine derivatives (6a–g) as side products in poor yields. All new compounds were fully characterized using different spectroscopic methods. Mass ESI-HMRS measurements were also performed. Furthermore, these compounds were screened for their in vitro cytotoxicity activities against three cancer cell lines; namely, those of the liver (line HepG2), prostate (line DU145) and breast (line MBA-MB-231). The cytotoxicity assessment revealed that compounds 5d, 5g, 5h and 5i exhibit promising antiproliferative effects (IC50 1–5 µM) against those three cancer cell lines.

scholarly journals Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1789 ◽  
Author(s):  
Julia Krzywik ◽  
Witold Mozga ◽  
Maral Aminpour ◽  
Jan Janczak ◽  
Ewa Maj ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Docking Studies ◽  
Binding Modes ◽  
Colchicine Binding Site ◽  
3T3 Cell Lines ◽  
Colchicine Derivatives

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

scholarly journals Synthesis and anti-acetylcholinesterase activities of novel glycosyl coumarylthiazole derivatives

2020 ◽  
pp. 174751982094835
Author(s):  
You-Xian Wang ◽  
Shu-Hao Liu ◽  
Zhong-Bai Shao ◽  
Lian-Gong Cao ◽  
Kai-Jun Jiang ◽  
...  
Keyword(s):  
Electrospray Ionization ◽  
New Products ◽  
Reaction Conditions ◽  
Inhibitory Rate ◽  
Inhibitory Activities ◽  
Ellman’S Method ◽  
New Compounds ◽  
C Nmr

Eleven glycosyl coumarylthiazole derivatives are synthesized by cyclization and condensation of glycosyl thiourea with 3-bromoacetyl coumarins in ethanol. The reaction conditions are optimized and good yields of products (80%–95%) are obtained. The structures of all new products were confirmed by IR, 1H and 13C NMR, and by HRMS (electrospray ionization). The in vitro acetylcholinesterase (AChE) inhibitory activities of these new compounds are tested by Ellman’s method. Among them, N-(2-acetamido-3,4,6-tri- O-acetyl-2-deoxy-β-D-glucopyranosyl)-4-(6-nitrocoumarinyl)-1,3-thiazole-2-amine showed the best activity with an in vitro AChE inhibitory rate of 58% and an IC50 value of 12 ± 0.38 μg/mL.

scholarly journals Synthesis, Characterization, and Biological Activity of a Novel Series of Benzo[4,5]imidazo[2,1-b]thiazole Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 682 ◽  
Author(s):  
Xinshan Deng ◽  
Xiaoyu Tan ◽  
Tiantian An ◽  
Qingqing Ma ◽  
Zhe Jin ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Normal Cell ◽  
Growth Factor Receptor ◽  
Human Cell Line ◽  
Thiazole Derivatives ◽  
Cellular Toxicity ◽  
Epidermal Growth ◽  
Inhibitory Activities

Based on the analysis of epidermal growth factor receptor (EGFR) complexes with gefitinib with molecular docking, the scaffold-hopping strategy, combination of the active substructures, and structural optimization of EGFR inhibitors, a novel series of benzo[4,5]imidazo[2,1-b]thiazole derivatives was designed, synthesized, and evaluated for antitumor activity in human cancer cell lines and cellular toxicity against human normal cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and EGFR inhibitory activities in vitro. Some target compounds such as 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(2-hydroxyphenyl)acetamide (D04) and 2-(benzo[4,5]imidazo[2,1-b]thiazol-3-yl)-N-(naphthalen-1-yl)acetamide (D08) have shown significant antitumor activity against the EGFR high-expressed human cell line HeLa. All the target compounds showed hardly any antitumor activity against the EGFR low-expressed human cell line HepG2, and nearly no cellular toxicity against the human normal cell lines HL7702 and human umbilical vein endothelial cell lines (HUVEC). The inhibitory activities against EGFR kinase in vitro of the three target compounds were greatly consistent with the anti-proliferative activities. The preliminary structure–activity relationships of the target compounds were summarized. Conclusively, the novel benzo[4,5]imidazo[2,1-b]thiazole derivatives as novel potential EGFR inhibitors may be used as the potential lead compounds for the development of antitumor agents.

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