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

被引：17

作者：

Goncalves, Itamar Luis ^{[1
]}

Rockenbach, Liliana ^{[1
]}

das Neves, Gustavo Machado ^{[1
]}

Goethel, Gabriela ^{[2
]}

Nascimento, Fabiana ^{[1
]}

Kagami, Luciano Porto ^{[1
]}

Figueiro, Fabricio ^{[3
]}

de Azambuja, Gabriel Oliveira ^{[1
]}

Dias, Amanda de Fraga ^{[3
]}

Amaro, Andressa ^{[3
]}

de Souza, Lauro Mera ^{[4
]}

Pitta, Ivan da Rocha ^{[5
]}

Avila, Daiana Silva ^{[6
]}

Kawano, Daniel Fabio ^{[7
]}

Garcia, Solange Cristina ^{[2
]}

Oliveira Battastinic, Ana Maria ^{[3
]}

Eifler-Lima, Vera Lucia ^{[1
]}

机构：

[1] Univ Fed Rio Grande do Sul, Fac Farm, Lab Sintese Organ Med LaSOM, Ave Ipiranga 2752, Porto Alegre, RS, Brazil

[2] Univ Fed Rio Grande do Sul, Fac Farm, Lab Toxicol LATOX, Porto Alegre, RS, Brazil

[3] Univ Fed Rio Grande do Sul, ICBS, Dept Bioquim, Porto Alegre, RS, Brazil

[4] Fac Pequeno Principe, Inst Pesquisa Pele Pequeno Principe, Curitiba, PR, Brazil

[5] Univ Fed Pernambuco, Nucleo Pesquisa Inovacao Terapeut, Recife, PE, Brazil

[6] Univ Fed Pampa UNIPAMPA, Grp Pesquisa Bioquim & Toxicol Caenorhabditis Ele, Uruguaiana, RS, Brazil

[7] Univ Estadual Campinas, Fac Ciencias Farmaceut, Campinas, SP, Brazil

来源：

MEDCHEMCOMM | 2018年 / 9卷 / 06期

关键词：

SPINDLE PROTEIN; BIGINELLI REACTION; ACCURATE DOCKING; POTENT; DIHYDROPYRIMIDINES; EPIDEMIOLOGY; GLIOBLASTOMA; VALIDATION; EXPRESSION; COMPOUND;

D O I：

10.1039/c8md00095f

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 G(2)/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to Caenorhabditis elegans.

引用

页码：995 / 1010

页数：16

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