One pot synthesis, in silico study and evaluation of some novel flavonoids as potent topoisomerase II inhibitors

Abstract Background Etoposide is one of the most potential anti-cancerous drugs that targets topoisomerase II (topoII) and inhibits its activity by ligation with the DNA molecule. Results In silico study confirmed that the etoposide-binding sites of topoII are conserved among the plants and human. The efficacy of the drug on plant system was initially assessed using germinated grass pea (Lathyrus sativus L.) seedlings (in vivo) in relation to radicle length and mitotic index. The callus system (in vitro) was also used to elucidate the effect of etoposide on callus growth kinetics. Furthermore, it was observed that etoposide able to inhibit the division of polyploid cells induced by colchicine treatment (0.5%, 8 h). To determine the molecular interaction, topoII was isolated from young grass pea leaves using polyethylene glycol fractionation and ammonium sulphate precipitation followed by column chromatography on CM-Sephadex (C-25). The plasmid linearization assays by isolated plant topoII in the presence of etoposide significantly revealed the functional similarity of plants and human topoII. Results indicated that the effect of etoposide on plant topoII is significant. Conclusions This study may pave the way to develop a plant-based assay system for screening the topoisomerase targeted anti-cancerous drugs, as it is convenient and cost-effective.

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A one-pot, efficient and facile synthesis of 4β-arylaminopodophyllotoxins: synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors

Tetrahedron Letters ◽

10.1016/j.tetlet.2003.09.110 ◽

2003 ◽

Vol 44 (46) ◽

pp. 8457-8459 ◽

Cited By ~ 30

Author(s):

Ahmed Kamal ◽

B.Ashwini Kumar ◽

M. Arifuddin

Keyword(s):

Topoisomerase Ii ◽

Dna Topoisomerase Ii ◽

Facile Synthesis ◽

One Pot ◽

Dna Topoisomerase ◽

Topoisomerase Ii Inhibitors

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Molecular docking studies, in-silico ADMET screening, MM-GBSA binding free energy of some novel chalcone substituted 9-anilinoacridines as topoisomerase II inhibitors

International Journal of Computational Biology and Drug Design ◽

10.1504/ijcbdd.2020.10033058 ◽

2020 ◽

Vol 13 (4) ◽

pp. 347

Author(s):

G. Rathika ◽

A. Pandiselvi ◽

Rajagopal Kalirajan ◽

K. Iniyavan

Keyword(s):

Free Energy ◽

Molecular Docking ◽

In Silico ◽

Topoisomerase Ii ◽

Binding Free Energy ◽

Docking Studies ◽

Molecular Docking Studies ◽

Topoisomerase Ii Inhibitors ◽

In Silico Admet

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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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