Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

AbstractDue to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K b) for the ligand, copper and nickel complexes were 2.09 × 104 M-1, 2.37 × 104 M-1 and 2.11 × 104 M-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.

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Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors

Zeitschrift für Naturforschung C ◽

10.1515/znc-2020-0104 ◽

2020 ◽

Vol 75 (9-10) ◽

pp. 353-362

Author(s):

Begüm Nurpelin Sağlık ◽

Ahmet Mücahit Şen ◽

Asaf Evrim Evren ◽

Ulviye Acar Çevik ◽

Derya Osmaniye ◽

...

Keyword(s):

Anticancer Activity ◽

In Silico ◽

Biological Effects ◽

Docking Studies ◽

Benzimidazole Derivatives ◽

Binding Modes ◽

Reference Drug ◽

In Silico Studies ◽

New Compounds ◽

Mcf 7

AbstractInhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

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Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2021.1945591 ◽

2021 ◽

Vol 36 (1) ◽

pp. 1732-1750

Author(s):

Mohammed M. Alanazi ◽

Elwan Alaa ◽

Nawaf A. Alsaif ◽

Ahmad J. Obaidullah ◽

Hamad M. Alkahtani ◽

...

Keyword(s):

In Silico ◽

Design Synthesis ◽

In Silico Studies ◽

Anti Cancer

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Shedding Light on the Interaction of Human Anti-Apoptotic Bcl-2 Protein with Ligands through Biophysical and in Silico Studies

International Journal of Molecular Sciences ◽

10.3390/ijms20040860 ◽

2019 ◽

Vol 20 (4) ◽

pp. 860 ◽

Cited By ~ 2

Author(s):

Joao Ramos ◽

Jayaraman Muthukumaran ◽

Filipe Freire ◽

João Paquete-Ferreira ◽

Ana Otrelo-Cardoso ◽

...

Keyword(s):

Conformational Changes ◽

In Silico ◽

Nucleotide Polymorphisms ◽

Ligand Interaction ◽

Zinc Database ◽

In Silico Studies ◽

Anti Cancer ◽

Binding Groove ◽

The Stability ◽

Dynamics Simulations

Bcl-2 protein is involved in cell apoptosis and is considered an interesting target for anti-cancer therapy. The present study aims to understand the stability and conformational changes of Bcl-2 upon interaction with the inhibitor venetoclax, and to explore other drug-target regions. We combined biophysical and in silico approaches to understand the mechanism of ligand binding to Bcl-2. Thermal shift assay (TSA) and urea electrophoresis showed a significant increase in protein stability upon venetoclax incubation, which is corroborated by molecular docking and molecular dynamics simulations. An 18 °C shift in Bcl-2 melting temperature was observed in the TSA, corresponding to a binding affinity multiple times higher than that of any other reported Bcl-2 inhibitor. This protein-ligand interaction does not implicate alternations in protein conformation, as suggested by SAXS. Additionally, bioinformatics approaches were used to identify deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) of Bcl-2 and their impact on venetoclax binding, suggesting that venetoclax interaction is generally favored against these deleterious nsSNPs. Apart from the BH3 binding groove of Bcl-2, the flexible loop domain (FLD) also plays an important role in regulating the apoptotic process. High-throughput virtual screening (HTVS) identified 5 putative FLD inhibitors from the Zinc database, showing nanomolar affinity toward the FLD of Bcl-2.

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Ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Molbank ◽

10.3390/m1029 ◽

2018 ◽

Vol 2018 (4) ◽

pp. M1029 ◽

Cited By ~ 1

Author(s):

Itamar Gonçalves ◽

Luciano Porto Kagami ◽

Gustavo Machado das Neves ◽

Liliana Rockenbach ◽

Leonardo Davi ◽

...

Keyword(s):

In Silico ◽

Biginelli Reaction ◽

Cancer Drugs ◽

Biological Targets ◽

In Silico Studies ◽

Anti Cancer ◽

Privileged Structure ◽

Good Potential

The Biginelli reaction is a highly versatile reaction that leads to dihydropyrimidinones/thiones. This scaffold is reported as being a privileged structure due to its ability to interact with biological targets. Synthesis of ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate was achieved through the Biginelli reaction using a functionalized thiourea. In silico studies demonstrated that the compound title showed good potential for interacting with ecto-5’-nucleotidase, which has been considered as a target in designs for anti-cancer drugs.

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The new metal-based compound from anticancer drug cytarabine: Spectral, electrochemical, DNA-binding, antiproliferative effect and in silico studies

Journal of Molecular Structure ◽

10.1016/j.molstruc.2019.05.014 ◽

2019 ◽

Vol 1193 ◽

pp. 532-543 ◽

Cited By ~ 1

Author(s):

Özge Güngör ◽

Mustafa Çeşme ◽

M. Emin Çınar ◽

Ayşegül Gölcü

Keyword(s):

Dna Binding ◽

Anticancer Drug ◽

In Silico ◽

Antiproliferative Effect ◽

In Silico Studies

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Discovery of a novel DNA binding agent via design and synthesis of new thiazole hybrids and fused 1,2,4-triazines as potential antitumor agents: Computational, spectrometric and in silico studies

Bioorganic Chemistry ◽

10.1016/j.bioorg.2019.103089 ◽

2019 ◽

Vol 90 ◽

pp. 103089 ◽

Cited By ~ 4

Author(s):

Marwa H. El-Wakil ◽

Amira F. El-Yazbi ◽

Hayam M.A. Ashour ◽

Mounir A. Khalil ◽

Khadiga A. Ismail ◽

...

Keyword(s):

Dna Binding ◽

In Silico ◽

Antitumor Agents ◽

Binding Agent ◽

Design And Synthesis ◽

In Silico Studies ◽

Potential Antitumor

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Synthesis and In Vitro Evaluation of Tetrahydroquinoline Derivatives as Antiproliferative Compounds of Breast Cancer via Targeting the GPER

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666181119094144 ◽

2019 ◽

Vol 19 (6) ◽

pp. 760-771 ◽

Cited By ~ 2

Author(s):

Oscar J. Zacarías-Lara ◽

David Méndez-Luna ◽

Gustavo Martínez-Ruíz ◽

José R. García-Sanchéz ◽

Manuel J. Fragoso-Vázquez ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cell Lines ◽

In Silico ◽

Breast Cancer Cells ◽

Breast Cancer Cell Lines ◽

In Silico Studies ◽

Mcf 7

Background: Some reports have demonstrated the role of the G Protein-coupled Estrogen Receptor (GPER) in growth and proliferation of breast cancer cells. Objective: In an effort to develop new therapeutic strategies against breast cancer, we employed an in silico study to explore the binding modes of tetrahydroquinoline 2 and 4 to be compared with the reported ligands G1 and G1PABA. Methods: This study aimed to design and filter ligands by in silico studies determining their Lipinski's rule, toxicity and binding properties with GPER to achieve experimental assays as anti-proliferative compounds of breast cancer cell lines. Results: In silico studies suggest as promissory two tetrahydroquinoline 2 and 4 which contain a carboxyl group instead of the acetyl group (as is needed for G1 synthesis), which add low (2) and high hindrance (4) chemical moieties to explore the polar, hydrophobic and hindrance effects. Docking and molecular dynamics simulations of the target compounds were performed with GPER to explore their binding mode and free energy values. In addition, the target small molecules were synthesized and assayed in vitro using breast cancer cells (MCF-7 and MDA-MB-231). Experimental assays showed that compound 2 decreased cell proliferation, showing IC50 values of 50µM and 25µM after 72h of treatment of MCF-7 and MDA-MB-231 cell lines, respectively. Importantly, compound 2 showed a similar inhibitory effect on proliferation as G1 compound in MDA-MB-231 cells, suggesting that both ligands reach the GPER-binding site in a similar way, as was demonstrated through in silico studies. Conclusion: A concentration-dependent inhibition of cell proliferation occurred with compound 2 in the two cell lines regardless of GPER.

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