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

Abstract

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 3β-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.

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  • Authors+Show Affiliations

    ,

    Laboratório de Virologia Aplicada, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, 88040-970, Brazil.

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    Friedrich-Alexander-Universität, Lehrstuhl für Pharmazeutische Biologie, Staudtstr. 5, D-91058, Erlangen, Germany.

    ,

    Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    ,

    Laboratório de Virologia Aplicada, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, 88040-970, Brazil.

    ,

    Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    ,

    Friedrich-Alexander-Universität, Lehrstuhl für Pharmazeutische Biologie, Staudtstr. 5, D-91058, Erlangen, Germany.

    ,

    Departmento de Produção de Matéria-Prima, Faculdade de Farmácia, Universidade Federal de Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90610-000, Brazil.

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    Departmento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    ,

    Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    ,

    Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    ,

    Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, 31270-901, Brazil.

    Laboratório de Virologia Aplicada, Programa de Pós-Graduação em Farmácia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, 88040-970, Brazil. Electronic address: claudia.simoes@ufsc.br.

    Source

    European journal of medicinal chemistry 167: 2019 Apr 01 pg 546-561

    MeSH

    Antineoplastic Agents
    Antiviral Agents
    Cell Death
    Cell Line
    Cell Line, Tumor
    Click Chemistry
    Digitoxigenin
    Drug Screening Assays, Antitumor
    Glycosides
    Herpesviridae Infections
    Herpesvirus 1, Human
    Herpesvirus 2, Human
    Humans

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    30798081

    Citation

    Boff, Laurita, et al. "Potential Anti-herpes and Cytotoxic Action of Novel Semisynthetic Digitoxigenin-derivatives." European Journal of Medicinal Chemistry, vol. 167, 2019, pp. 546-561.
    Boff L, Munkert J, Ottoni FM, et al. Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives. Eur J Med Chem. 2019;167:546-561.
    Boff, L., Munkert, J., Ottoni, F. M., Zanchett Schneider, N. F., Ramos, G. S., Kreis, W., ... Oliveira Simões, C. M. (2019). Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives. European Journal of Medicinal Chemistry, 167, pp. 546-561. doi:10.1016/j.ejmech.2019.01.076.
    Boff L, et al. Potential Anti-herpes and Cytotoxic Action of Novel Semisynthetic Digitoxigenin-derivatives. Eur J Med Chem. 2019 Apr 1;167:546-561. PubMed PMID: 30798081.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives. AU - Boff,Laurita, AU - Munkert,Jennifer, AU - Ottoni,Flaviano Melo, AU - Zanchett Schneider,Naira Fernanda, AU - Ramos,Gabriela Silva, AU - Kreis,Wolfgang, AU - Fernandes de Andrade,Saulo, AU - Dias de Souza Filho,José, AU - Braga,Fernão Castro, AU - Alves,Ricardo José, AU - Maia de Pádua,Rodrigo, AU - Oliveira Simões,Cláudia Maria, Y1 - 2019/02/02/ PY - 2018/04/26/received PY - 2018/09/05/revised PY - 2019/01/29/accepted PY - 2019/2/25/pubmed PY - 2019/4/19/medline PY - 2019/2/25/entrez KW - Anti-herpes KW - Cardenolides KW - Cytotoxic KW - Digitoxigenin-derivatives SP - 546 EP - 561 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 167 N2 - 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 3β-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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/30798081/Potential_anti-herpes_and_cytotoxic_action_of_novel_semisynthetic_digitoxigenin-derivatives L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(19)30096-0 DB - PRIME DP - Unbound Medicine ER -