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

共 50 条

[31] Monastrol, a selective inhibitor of the mitotic kinesin Eg5, induces a distinctive growth profile of dendrites and axons in primary cortical neuron cultures
Yoon, SY
Choi, JE
Huh, JW
Hwang, O
Lee, HS
Hong, HN
Kim, D
CELL MOTILITY AND THE CYTOSKELETON, 2005, 60 (04): : 181 - 190
[32] Photo-Regulation of Cell Division using Photochromic Inhibitors for Kinesin Eg5
Sadakane, Kei
Ishikawa, Kumiko
Seo, Hideo
Tohyama, Kanako
Yamanoha, Banri
Maruta, Shinsaku
BIOPHYSICAL JOURNAL, 2013, 104 (02) : 476A - 476A
[33] Inhibition of Eg5 (kinesin-like 1) with antisense oligonucleotides leads to arrest in G2M of cell cyle.
Koller, E
Hirsch, S
Shepard, PJ
Dean, NM
CLINICAL CANCER RESEARCH, 2003, 9 (16) : 6221S - 6221S
[34] Combination of active and inactive siRNA targeting the mitotic kinesin Eg5 impairs silencing efficiency in several cancer cell lines
Formstecher, Etienne
Reverdy, Celine
Cholay, Mickael
Planquette, Cecile
Trouplin, Virginie
Lehrmann, Heike
Aresta, Sandra
Calabrese, Alessandra
Arar, Khalil
Daviet, Laurent
Colland, Frederic
OLIGONUCLEOTIDES, 2006, 16 (04) : 387 - 394
[35] Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5
Sun, Xiao-dong
Shi, Xing-juan
Sun, Xiao-ou
Luo, You-guang
Wu, Xiao-jing
Yao, Chang-fu
Yu, Hai-yang
Li, Deng-wen
Liu, Min
Zhou, Jun
ACTA PHARMACOLOGICA SINICA, 2011, 32 (12) : 1543 - 1548
[36] Dimethylenastron suppresses human pancreatic cancer cell migration and invasion in vitro via allosteric inhibition of mitotic kinesin Eg5
Xiao-dong Sun
Xing-juan Shi
Xiao-ou Sun
You-guang Luo
Xiao-jing Wu
Chang-fu Yao
Hai-yang Yu
Deng-wen Li
Min Liu
Jun Zhou
Acta Pharmacologica Sinica, 2011, 32 : 1543 - 1548
[37] Photo-Reversible Inhibition of Mitotic Kinesin Eg5 by Photochromic STLC Analogues Composed of Azobenzene
Tohyama, Kanako
Ishikawa, Kumiko
Maruta, Shinsaku
BIOPHYSICAL JOURNAL, 2014, 106 (02) : 780A - 780A
[38] The angiogenic cascade is down regulated by kinesin Eg5 inhibitors in gastric adenocarcinoma cell line
Ricci, A.
Gallorini, M.
Del Bufalo, D.
Cataldi, A.
D'Agostino, I.
Carradori, S.
Zara, S.
FEBS OPEN BIO, 2022, 12 : 215 - 215
[39] The Effect of Adjuvant Dimethylenastron, a Mitotic Kinesin Eg5 Inhibitor, in Experimental Glaucoma Filtration Surgery
Lueke, Julia
Nassar, Khaled
Lueke, Matthias
Tura, Ayceguel
Merz, Hartmut
Giannis, Athanassios
Grisanti, Salvatore
CURRENT EYE RESEARCH, 2010, 35 (12) : 1090 - 1098
[40] Monastrol-inhibition of a highly processive Kinesin5-head/Kinesin1-stalk chimera
Lakmper, S.
Korneev, M. J.
Reiter, S.
Kapitein, L. C. .
Peterman, E. J. G. .
Schmidt, C. F.
EUROPEAN JOURNAL OF CELL BIOLOGY, 2007, 86 : 9 - 9

← 1 2 3 4 5 →