In vitro and in silico studies of the interaction of three tetrazoloquinazoline derivatives with DNA and BSA and their cytotoxicity activities against MCF-7, HT-29 and DPSC cell lines

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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Biological Activity Evaluation and In Silico Studies of Polyprenylated Benzophenones from Garcinia celebica

Biomedicines ◽

10.3390/biomedicines9111654 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1654

Author(s):

Yenni Pintauli Pasaribu ◽

Arif Fadlan ◽

Sri Fatmawati ◽

Taslim Ersam

Keyword(s):

Antioxidant Activity ◽

Molecular Docking ◽

Cell Lines ◽

In Silico ◽

Oral Drug ◽

Root Bark ◽

Falciparum Strain ◽

In Silico Studies ◽

Mcf 7

This study aimed to isolate polyprenylated benzophenones from the rootbark of Garcinia celebica and assess their activities in vitro and in silico. The antioxidant activity was evaluated by the DPPH, ABTS, and FRAP methods. The cytotoxicity was evaluated against HeLa, MCF-7, A549, and B16 cancer cell lines. The antiplasmodial activity was performed against the chloroquine-sensitive Plasmodium falciparum strain 3D7. Molecular docking was analyzed on alpha-estrogen receptor (3ERT) and P. falciparum lactate dehydrogenase enzyme (1CET). The prediction of ADMET for the compounds was also studied. For the first time, (-)-cycloxanthochymol, isoxanthochymol, and xanthochymol were isolated from the root bark of Garcinia celebica. The antioxidant and cytotoxicity evaluation showed that all benzophenones exhibited antioxidant activity compared to gallic acid and quercetin as positive controls and also exhibited strong activity against HeLa, MCF-7, A549, and B16 cell lines compared to cisplatin as the positive control. The antiplasmodial evaluation showed that isoxanthochymol exhibited activity against the chloroquine-sensitive P. falciparum strain 3D7. In addition, the in silico molecular docking study supported in vitro activities. The ADMET analysis also indicated the isolated benzophenones are potential oral drug candidates.

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Novel N-bridged pyrazole-1-carbothioamides with potential antiproliferative activity: design, synthesis, in vitro and in silico studies

Future Medicinal Chemistry ◽

10.4155/fmc-2021-0066 ◽

2021 ◽

Vol 13 (20) ◽

pp. 1743-1766

Author(s):

Islam H El Azab ◽

Essa M Saied ◽

Alaa A Osman ◽

Amir E Mehana ◽

Hosam A Saad ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Antiproliferative Activity ◽

In Silico ◽

Human Cancer ◽

Cancer Cell Lines ◽

Molecular Docking Study ◽

In Silico Studies

Thiazole-substituted pyrazole is an important structural feature of many bioactive compounds, including antiviral, antitubercular, analgesic and anticancer agents. Herein we describe an efficient and facile approach for the synthesis of two series of 36 novel N-bridged pyrazole-1-phenylthiazoles. The antiproliferative activity of a set of representative compounds was evaluated in vitro against different human cancer cell lines. Among the identified compounds, compound 18 showed potent anticancer activity against the examined cancer cell lines. The in silico molecular docking study revealed that compound 18 possesses high binding affinity toward both SK1 and CDK2. Overall, these results indicate that compound 18 is a promising lead anticancer compound which may be exploited for development of antiproliferative drugs.

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Antiproliferative Benzoindazolequinones as Potential Cyclooxygenase-2 Inhibitors

Molecules ◽

10.3390/molecules24122261 ◽

2019 ◽

Vol 24 (12) ◽

pp. 2261 ◽

Cited By ~ 1

Author(s):

Aurora Molinari ◽

Alfonso Oliva ◽

Marlene Arismendi-Macuer ◽

Leda Guzmán ◽

Waldo Acevedo ◽

...

Keyword(s):

Cell Lines ◽

In Silico ◽

Antitumor Agents ◽

Human Cancer ◽

In Vitro Models ◽

Cyclooxygenase 2 ◽

Binding Energies ◽

Human Cancer Cells ◽

Mcf 7

Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of benzoindazolequinones (BIZQs), and to evaluate overexpressed proteins in human cancer cells as potential biomolecular targets of these compounds. For this purpose, this study was carried out using KATO-III and MCF-7 cell lines as in vitro models. Docking results showed that these BIZQs present better binding energies (ΔGbin) values for cyclooxygenase-2 (COX-2) than for other cancer-related proteins. The predicted ∆Gbin values of these BIZQs, classified in three series, positively correlated with IC50 measured in both cell lines (KATO-III: 0.72, 0.41, and 0.90; MCF-7: 0.79, 0.55, and 0.87 for Series I, II, and III, respectively). The results also indicated that compounds 2a, 2c, 6g, and 6k are the most prominent BIZQs, because they showed better IC50 and ∆Gbin values than the other derivatives. In silico drug absorption, distribution, metabolism, and excretion (ADME) properties of the three series were also analyzed and showed that several BIZQs could be selected as potential candidates for cancer pre-clinical assays.

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Prospects of Wedelolactone as a Chemotherapeutic Agent in Gynecological Cancers; Clue From its In Vitro and In Silico Investigation

Current Computer - Aided Drug Design ◽

10.2174/1573409915666191015113134 ◽

2020 ◽

Vol 16 (4) ◽

pp. 365-375

Author(s):

Sadia Sarwar ◽

Tauqeer Amed ◽

Neelum Gul Qazi ◽

Jun Qing Yu ◽

Fazlul Huq

Keyword(s):

Alkaline Phosphatase ◽

Cell Lines ◽

In Silico ◽

Topoisomerase Ii ◽

Tumor Models ◽

Growth Inhibitory ◽

In Silico Study ◽

Inhibitory Potential ◽

Mcf 7

Background: Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models. Objective: The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study. Methods: Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors. Results and Discussion: The IC50 value of WDL was 25.77 ± 4.82 μM and 33.64 ± 1.45 μM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB. Conclusion: We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

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Proanthocyanidins reduce cellular function in the most globally diagnosed cancers in vitro

PeerJ ◽

10.7717/peerj.9910 ◽

2020 ◽

Vol 8 ◽

pp. e9910

Author(s):

Sarah Albogami

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Colorimetric Assay ◽

Human Cancer ◽

Cancer Cell Lines ◽

Trypan Blue Exclusion Method ◽

Apoptotic Nucleus ◽

Ht 29 ◽

Mcf 7

Background Growing evidence indicates that proanthocyanidins (PACs) may be effective in treating and preventing various cancers. The fundamental mechanism of PACs inhibiting the proliferation at cellular and molecular levels in most of the cancer types remains unclear. Objective The anticancer efficacy of PACs was investigated in vitro using three human cancer cell lines: human colorectal adenocarcinoma (HT-29), human breast carcinoma (MCF-7), and human prostatic adenocarcinoma (PC-3). Methods Cytotoxicity was evaluated by MTT assay, while cell proliferation was measured by trypan blue exclusion method. Cell migration was measured by wound healing assay, and DAPI staining was used to evaluate apoptotic nucleus morphology. RT-PCR was used to analyze the expression of Bax and Bcl-2, and caspase enzyme activity assay was measured by caspase colorimetric assay. Results PACs could inhibit both cellular viability and proliferation in a concentration- and time-dependent fashion in all investigated cells. Further, all tested cells showed similarly decreased migration after 24- and 48-h PAC treatment. We observed increased apoptotic nucleus morphology in treated cells (p ≤ 0.01). BAX expression significantly increased in HT-29 (p < 0.01), PC-3(p < 0.01), and MCF-7 (p < 0.05) cells, while BCL-2 expression significantly declined (p < 0.05). Caspase activities were significantly increased in all tested cancer cell lines after 24-h PAC treatment. Conclusion PACs may have potential therapeutic properties against colorectal, breast, and prostate cancer.

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Design, Synthesis of novel coumarin conjugated acetamides as promising anticancer agents: An in-silico and in-vitro approach.

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200714140820 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mamatha S. V ◽

S. L. Belagali ◽

Mahesh Bhat ◽

Vijay M. Kumbar

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Mtt Assay ◽

Anticancer Agents ◽

In Silico ◽

Active Sites ◽

Biological Activities ◽

Biological Evaluation ◽

Mcf 7

Background: Coumarin and benzophenone possess a vast sphere of biological activities whereas thiazoles display various pharmacological properties. Hence we focused on incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity anticipating their interesting biological properties. Objective: The objective of the current work is synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. Methods: A novel series of Coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by multistep reaction sequence and were characterized by the FT-IR, LCMS and NMR spectral techniques. The newly synthesized compounds were screened for anticancer activity by in-silico and in-vitro methods. The cytotoxicity of the synthesized unique compounds had been executed for two different cancer cell lines MCF-7 (Breast cancer) and KB (Oral cancer) in comparison with standard paclitaxel by MTT assay. Results: The compound 7f is the potent motif with an acceptable range of IC 50 values for anticancer activity were 63.54 µg/ml and 55.67 µg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids MET 769, ARG 817 and LYS 721. Conclusion: Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.

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Facile One-Pot Multicomponent Synthesis of Pyrazolo-Thiazole Substituted Pyridines with Potential Anti-Proliferative Activity: Synthesis, In Vitro and In Silico Studies

Molecules ◽

10.3390/molecules26113103 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3103

Author(s):

Islam H. El El Azab ◽

Rania B. Bakr ◽

Nadia A. A. Elkanzi

Keyword(s):

Cell Lines ◽

In Silico ◽

Topoisomerase Ii ◽

Human Cancer ◽

Docking Simulation ◽

Cytotoxic Potential ◽

One Pot ◽

In Silico Docking ◽

In Silico Studies

Pyrazolothiazole-substituted pyridine conjugates are an important class of heterocyclic compounds with an extensive variety of potential applications in the medicinal and pharmacological arenas. Therefore, herein, we describe an efficient and facile approach for the synthesis of novel pyrazolo-thiazolo-pyridine conjugate 4, via multicomponent condensation. The latter compound was utilized as a base for the synthesis of two series of 15 novel pyrazolothiazole-based pyridine conjugates (5–16). The newly synthesized compounds were fully characterized using several spectroscopic methods (IR, NMR and MS) and elemental analyses. The anti-proliferative impact of the new synthesized compounds 5–13 and 16 was in vitro appraised towards three human cancer cell lines: human cervix (HeLa), human lung (NCI-H460) and human prostate (PC-3). Our outcomes regarding the anti-proliferative activities disclosed that all the tested compounds exhibited cytotoxic potential towards all the tested cell lines with IC50 = 17.50–61.05 µM, especially the naphthyridine derivative 7, which exhibited the most cytotoxic potential towards the tested cell lines (IC50 = 14.62–17.50 µM) compared with the etoposide (IC50 = 13.34–17.15 µM). Moreover, an in silico docking simulation study was performed on the newly prepared compounds within topoisomerase II (3QX3), to suggest the binding mode of these compounds as anticancer candidates. The in silico docking results indicate that compound 7 was a promising lead anticancer compound which possesses high binding affinity toward topoisomerase II (3QX3) protein.

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An In Vitro and In Silico Study of the Enhanced Antiproliferative and Pro-Oxidant Potential of Olea europaea L. cv. Arbosana Leaf Extract via Elastic Nanovesicles (Spanlastics)

Antioxidants ◽

10.3390/antiox10121860 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1860

Author(s):

Taghreed S. Alnusaire ◽

Ahmed M. Sayed ◽

Abeer H. Elmaidomy ◽

Mohammad M. Al-Sanea ◽

Sarah Albogami ◽

...

Keyword(s):

Cell Lines ◽

Antiproliferative Activity ◽

In Silico ◽

Olea Europaea ◽

Leaf Extract ◽

Olea Europaea L ◽

In Silico Study ◽

Mcf 7 ◽

Olea Europaéa

The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC50 values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC50 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC50 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.

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Structure-Activity Relationship Study of an Alkynylphosphonate and a Vynilphosphonate Analogues of Calcitriol

Medicinal Chemistry ◽

10.2174/1573406416999200818145115 ◽

2020 ◽

Vol 16 ◽

Author(s):

Silvina Mariela Grioli ◽

Eliana Noelia Alonso ◽

Evangelina Mascaró ◽

Santiago Armando Stabile ◽

María Julia Ferronato ◽

...

Keyword(s):

Cell Lines ◽

In Silico ◽

Rational Design ◽

Parent Compound ◽

In Vitro Assays ◽

Antitumoral Activity ◽

Lateral Side ◽

Antitumor Effects ◽

In Silico Studies

Background: 1α,25-dihydroxyvitamin D3 (calcitriol) shows potent growth-inhibitory properties on different can-cer cell lines but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important todevelop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG. Objective: The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyse by in silico studies the chemical structure-biological function relationship of these molecules. Methods: We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modelling. Results: The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor ac-tivity was blunted, as no antiproliferative or antimigratory effects were observed. By in silico assays, we demostrated that SG analogue has lower affinity for the VDR-ligand binding domain than EM1 compound, due to lack of interaction with the important residues His305 and His397. Conclusion: These results demonstrate that chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.

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