Dataset Information

Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

ABSTRACT: An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called 20h and 20e, with an anti-proliferative effects, achieving IC50 values of about half that of the IC50 of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the 20e and 20h compounds induced cell cycle arrest in the G2/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to Caenorhabditis elegans.

SUBMITTER: Goncalves IL

PROVIDER: S-EPMC6072436 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

Gonçalves Itamar Luís IL Rockenbach Liliana L das Neves Gustavo Machado GM Göethel Gabriela G Nascimento Fabiana F Porto Kagami Luciano L Figueiró Fabrício F Oliveira de Azambuja Gabriel G de Fraga Dias Amanda A Amaro Andressa A de Souza Lauro Mera LM da Rocha Pitta Ivan I Avila Daiana Silva DS Kawano Daniel Fábio DF Garcia Solange Cristina SC Battastini Ana Maria Oliveira AMO Eifler-Lima Vera Lucia VL

MedChemComm 20180417 6

An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called <b>20h</b> and <b>20e</b>, with an anti-proliferative effects, ...[more]

PMID: 30108989

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Project description:Breast cancer is a complex heterogeneous disease and is one of the leading causes of death among women. In addressing the need for treatments of this life-threatening illness, we studied 3,4-dihydropyrimidin-2(1H)-one (or thione) derivatives (DHPMs), a class of inhibitor molecules of the Eg5 motor spindle protein that shows pronounced antitumor activity against several cancer cell lines.An in vitro screening was performed for identification of DHPMs with potent antitumor effects on MCF-7 and MDA-MB-231 cells and the selected DHPMs were evaluated for their inhibitory activity on Eg5 both in silico, using Molecular dynamics, and in vitro Eg5 inhibition assays. Analysis of cell death induction, proliferation, cell cycle and cancer stem cells (CSC) profile were performed by flow cytometry to assess the influence of the selected DPHMs on these important tumor features. Finally, the effects of DHPM treatment on tube formation were evaluated in vitro using HUVEC cells, and in vivo using a model on chorioallantoic membrane (CAM) of fertilized eggs.We identified five DHPMs with pronounced inhibitory activity on Eg5 motor protein interfering with the proper mitotic spindle assembly during cell division. These compounds impair the correct conclusion of cell cycle of the breast cancer cells and showed to be selective for tumor cells. Moreover, DHPMs modulate the CD44(+)/CD24(-) phenotype leading to a decrease in the CSC population in MDA-MB-231 cells, an important effect since CSC are resistant to many conventional cancer therapies and play a pivotal role in tumor initiation and maintenance. This observation was confirmed by the results which demonstrated that DHPM treated cells had impaired proliferation and were unable to sustain angiogenesis events. Finally, the DHMP treated cells were induced to apoptosis, which is one of the most pursued goals in drug development.The results of our study strongly suggest that DHPMs inhibit important tumorigenic features of breast cancer cells leading them to death by apoptosis. These findings firmly point to DHPM molecular architecture as a promising alternative against breast cancer.

Dataset Information

Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

Publications

Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

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