Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives

被引:21
作者
Boff, Laurita [1 ]
Munkert, Jennifer [2 ]
Ottoni, Flaviano Melo [3 ]
Zanchett Schneider, Naira Fernanda [1 ]
Ramos, Gabriela Silva [3 ]
Kreis, Wolfgang [2 ]
de Andrade, Saulo Fernandes [4 ]
de Souza Filho, Jose Dias [5 ]
Braga, Fernao Castro [3 ]
Alves, Ricardo Jose [3 ]
de Padua, Rodrigo Maia [3 ]
Oliveira Simoes, Claudia Maria [1 ]
机构
[1] Univ Fed Santa Catarina, Programa Posgrad Farm, Lab Virol Aplicada, BR-88040970 Florianopolis, SC, Brazil
[2] Friedrich Alexander Univ, Lehrstuhl Pharmazeut Biol, Staudtstr 5, D-91058 Erlangen, Germany
[3] Univ Fed Minas Gerais, Fac Farm, Dept Prod Farmaceut, BR-31270901 Belo Horizonte, MG, Brazil
[4] Univ Fed Rio Grande do Sul, Fac Farm, Dept Prod Mat Prima, BR-90610000 Porto Alegre, RS, Brazil
[5] Univ Fed Minas Gerais, Inst Ciencias Exatas, Dept Quim, BR-31270901 Belo Horizonte, MG, Brazil
关键词
Cardenolides; Digitoxigenin-derivatives; Anti-herpes; Cytotoxic; LUNG-CANCER CELLS; CARDIAC-GLYCOSIDES; CARDENOLIDE ANALOG; MANNOSE RECEPTOR; ATPASE; MONODIGITOXOSIDE; CONVALLATOXIN; AMANTADIG; NA; GLUCOEVATROMONOSIDE;
D O I
10.1016/j.ejmech.2019.01.076
中图分类号
R914 [药物化学];
学科分类号
100705 [微生物与生化药学];
摘要
In recent years, new therapeutic possibilities were proposed for cardiac glycosides traditionally used to treat heart diseases, such as anticancer and antiviral activities. In this sense, this work aimed to synthesize the readily accessible 3 beta-azido-3-deoxydigitoxigenin (5) from digitoxigenin (1). Two new series of compounds were obtained from derivative (5): (i) O-glycosyl trizols through click chemistry with propargyl glycosides; and (ii) compounds substituted in the alpha carbonyl position with different residues linked via an amino-group. All obtained derivatives have their chemical structures confirmed, and their anti-herpes (against HSV-types 1 and 2 replication) and cytotoxic (against PC3, A549, HCT-8 and LNCaP cell lines) activities evaluated. Compounds 10 and 11 exhibited the most promising results against HSV-1 (KOS and 29-R strains) and HSV-2 (333 strain) replication with SI values > 1000. Both compounds were also the most cytotoxic for the human cancer cell lines tested with IC50 values similar to those of paclitaxel. They also presented reduced toxicity toward non-cancerous cell lines (MRC-5 and HGF cells). Promising compounds were tested in regard to their ability to inhibit Na+/K+-ATPase. The inhibition rate correlates suitably with the bioactivity demonstrated by those both compounds against the different human cancer cells tested as well as against HSV replication. Moreover, the results showed that specific chemical features of compound 10 and 11 influenced the bioactivities tested. In summary, it was possible to obtain novel digitoxigenin-derivatives with remarkable cytotoxic and anti-herpes activities as well as low toxicity and high selectivity. In this way, they could be considered potential molecules for the development of new drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:546 / 561
页数:16
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