New Alkoxy Flavone Derivatives Targeting Caspases: Synthesis and Antitumor Activity Evaluation

被引:17
作者
Moreira, Joana [1 ,2 ]
Ribeiro, Diana [3 ]
Silva, Patricia M. A. [3 ]
Nazareth, Nair [4 ]
Monteiro, Madalena [4 ]
Palmeira, Andreia [1 ,2 ]
Saraiva, Lucilia [4 ]
Pinto, Madalena [1 ,2 ]
Bousbaa, Hassan [2 ,3 ]
Cidade, Honorina [1 ,2 ]
机构
[1] Univ Porto, Fac Pharm, Dept Chem Sci, Lab Organ & Pharmaceut Chem, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal
[2] Univ Porto, Interdisciplinary Ctr Marine & Environm Res CIIMA, Terminal Cruzeiros Porto Leixoes, Av Gen Norton de Matos S-N, P-4450208 Matosinhos, Portugal
[3] Inst Res & Adv Training Hlth Sci & Technol IINFAC, CESPU, Rua Cent Gandra 1317, P-4585116 Gandra, Portugal
[4] Univ Porto, Fac Pharm, Dept Biol Sci, LAQV REQUIMTE,Lab Microbiol, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal
来源
MOLECULES | 2019年 / 24卷 / 01期
关键词
flavonoids; O-heterocycles; alkylation; antitumor activity; apoptosis; caspase activators; ALLOSTERIC SITE; CELL-CYCLE; BAICALEIN; QSAR; CHRYSIN; ACTIVATORS; APOPTOSIS; CHALCONE; GROWTH;
D O I
10.3390/molecules24010129
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
The antitumor activity of natural flavonoids has been exhaustively reported. Previously it has been demonstrated that prenylation of flavonoids allows the discovery of new compounds with improved antitumor activity through the activation of caspase-7 activity. The synthesis of twenty-five flavonoids (4-28) with one or more alkyl side chains was carried out. The synthetic approach was based on the reaction with alkyl halide in alkaline medium by microwave (MW) irradiation. The in vitro cell growth inhibitory activity of synthesized compounds was investigated in three human tumor cell lines. Among the tested compounds, derivatives 6, 7, 9, 11, 13, 15, 17, and 18 revealed potent growth inhibitory activity (GI(50) < 10 M), being the growth inhibitory effect of compound 13 related with a pronounced caspase-7 activation on MCF-7 breast cancer cells and yeasts expressing human caspase-7. A quantitative structure-activity relationship (QSAR) model predicted that hydrophilicity, pattern of ring substitution/shape, and presence of partial negative charged atoms were the descriptors implied in the growth inhibitory effect of synthesized compounds. Docking studies on procaspase-7 allowed predicting the binding of compound 13 to the allosteric site of procaspase-7.
引用
收藏
页数:19
相关论文
共 43 条
  • [1] Beware of R2: Simple, Unambiguous Assessment of the Prediction Accuracy of QSAR and QSPR Models
    Alexander, D. L. J.
    Tropsha, A.
    Winkler, David A.
    [J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2015, 55 (07) : 1316 - 1322
  • [2] [Anonymous], 2011, Int J Drug Des Discov, DOI DOI 10.1016/JIJDDD.2011.07.007
  • [3] [Anonymous], 2004, CODESSA VERSION 2 7
  • [4] [Anonymous], NAT PROD LETT
  • [5] Targeting the MDM2-p53 protein-protein interaction with prenylchalcones: Synthesis of a small library and evaluation of potential antitumor activity
    Brandao, Pedro
    Loureiro, Joana B.
    Carvalho, Sylvie
    Hamadou, Meriem Hadjer
    Cravo, Sara
    Moreira, Joana
    Pereira, Daniela
    Palmeira, Andreia
    Pinto, Madalena
    Saraiva, Lucilia
    Cidade, Honorina
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 156 : 711 - 721
  • [6] Dietary Flavonoids and the Risk of Colorectal Cancer: An Updated Meta-Analysis of Epidemiological Studies
    Chang, Hui
    Lei, Lin
    Zhou, Yun
    Ye, Fayin
    Zhao, Guohua
    [J]. NUTRIENTS, 2018, 10 (07):
  • [7] Effect of baicalein on apoptosis of the human Hep G2 cell line was induced by mitochondria dysfunction
    Chang, WH
    Chen, CH
    Gaul, RJ
    Lin, CC
    Tsai, CL
    Tsai, K
    Lu, FJ
    [J]. PLANTA MEDICA, 2002, 68 (04) : 302 - 306
  • [8] Chen H., 2016, BAICALEIN DERIVATIVE, Patent No. CN 201610685066
  • [9] Synthesis and α-glucosidase inhibitory activity of chrysin, diosmetin, apigenin, and luteolin derivatives
    Cheng, Ning
    Yi, Wen-Bin
    Wang, Qi-Qin
    Peng, Sheng-Ming
    Zou, Xiao-Qing
    [J]. CHINESE CHEMICAL LETTERS, 2014, 25 (07) : 1094 - 1098
  • [10] Cidade H., 2017, APOPTOSIS