Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells

被引:14
作者
Chouchou, Adrien [1 ]
Patinote, Cindy [1 ,2 ]
Cuq, Pierre [1 ]
Bonnet, Pierre-Antoine [1 ]
Deleuze-Masquefa, Carine [1 ]
机构
[1] Univ Montpellier, ENSCM, IBMM, CNRS, F-34000 Montpellier, France
[2] CSU, Soc Accelerat Transfert Technol SATT AxLR, 950 Rue St Priest, F-34090 Montpellier, France
关键词
imidazo[1,2-a]quinoxaline; melanoma; imiqualine; A375 structure-activity relationship; BETULINIC ACID; IN-VITRO; SOLUBILITY;
D O I
10.3390/molecules23112987
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
Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability.
引用
收藏
页数:26
相关论文
共 26 条
[1]   Prodrug approach: An overview of recent cases [J].
Abet, Valentina ;
Filace, Fabiana ;
Recio, Javier ;
Alvarez-Builla, Julio ;
Burgos, Carolina .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 127 :810-827
[2]  
Avdeef Alex, 2001, Current Topics in Medicinal Chemistry, V1, P277, DOI 10.2174/1568026013395100
[3]   Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells [J].
Basken, Joel ;
Stuart, Scott A. ;
Kavran, Andrew J. ;
Lee, Thomas ;
Ebmeier, Christopher C. ;
Old, William M. ;
Ahn, Natalie G. .
MOLECULAR & CELLULAR PROTEOMICS, 2018, 17 (04) :550-564
[4]   Using Measured pKa, LogP and Solubility to Investigate Supersaturation and Predict BCS Class [J].
Box, K. J. ;
Comer, J. E. A. .
CURRENT DRUG METABOLISM, 2008, 9 (09) :869-878
[5]   Liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitative estimation of new imiqualine leads with potent anticancer activities in rat and mouse plasma. Application to a pharmacokinetic study in mice [J].
Chouchou, Adrien ;
Marion, Benedicte ;
Enjalbal, Christine ;
Roques, Celine ;
Cuq, Pierre ;
Bonnet, Pierre-Antoine ;
Bressolle-Gomeni, Francoise M. M. ;
Deleuze-Masquefa, Carine .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2018, 148 :369-379
[6]  
Deleuze-Masquefa C, 2009, Patent WO, Patent No. [2009043934 A1, 2009043934, WO2009043934 A1]
[7]  
Deleuze-Masquefa C., 2016, U.S. Patent, Patent No. [WO2016107895 A1, 2016107895, WO/2016/107895]
[8]   New imidazo[1,2-a]quinoxaline derivatives: Synthesis and in vitro activity against human melanoma [J].
Deleuze-Masquefa, Carine ;
Moarbess, Georges ;
Khier, Sonia ;
David, Nadege ;
Gayraud-Paniagua, Stephanie ;
Bressolle, Francoise ;
Pinguet, Frederic ;
Bonnet, Pierre-Antoine .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (09) :3406-3411
[9]   Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells [J].
Drag-Zalesinska, Malgorzata ;
Kulbacka, Julita ;
Saczko, Jolanta ;
Wysocka, Teresa ;
Zabel, Maciej ;
Surowiak, Pawel ;
Drag, Marcin .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (16) :4814-4817
[10]   Cutaneous melanoma [J].
Eggermont, Alexander M. M. ;
Spatz, Alan ;
Robert, Caroline .
LANCET, 2014, 383 (9919) :816-827