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Medchemcomm. 2018 Apr 17;9(6):995-1010. doi: 10.1039/c8md00095f. eCollection 2018 Jun 1.

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

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Laboratório de Síntese Orgânica Medicinal/LaSOM , Faculdade de Farmácia , Universidade Federal do Rio Grande do Sul , Avenida Ipiranga , 2752 , Porto Alegre/RS , Brazil . Email:
Laboratório de Toxicologia - LATOX , Faculdade de Farmácia , Universidade Federal do Rio Grande do Sul , Porto Alegre/RS , Brazil.
Departamento de Bioquímica , ICBS , Universidade Federal do Rio Grande do Sul , Porto Alegre/RS , Brazil . Email:
Instituto de Pesquisa Pelé Pequeno Príncipe , Faculdades Pequeno Príncipe , Curitiba-PR , Brazil.
Núcleo de Pesquisa em Inovação Terapêutica , Universidade Federal de Pernambuco , Recife/PE , Brazil.
Grupo de Pesquisa em Bioquímica e Toxicologia em Caenorhabditis elegans (GBToxCE) , Universidade Federal do Pampa-UNIPAMPA , Uruguaiana , RS , Brazil.
Faculdade de Ciências Farmacêuticas , Universidade Estadual de Campinas , Campinas-SP , Brazil.


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.

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