γ-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect

Alves, Silmara L.G.; Paixão, Natasha; Ferreira, Letícia Gonçalves Resende; Santos, Felipe Rocha da Silva; Neves, Luiza D.R.; Oliveira, Gisele Capanema de; Cortes, Vanessa Faria; Salomé, Kahlil Schwanka; Barison, Andersson; Santos, Fábio V.; Cenzi, Gisele; Varotti, Fernando P.; Oliveira, Soraya M.F.; Taranto, Alex Gutterres; Comar, Moacyr; Silva, Luciana M.; Noël, François; Quintas, Luis Eduardo M.; Barbosa, Leandro A.; Villar, José Augusto Ferreira Perez

doi:10.1016/j.bmc.2015.06.028

Cited by 15 publications

(12 citation statements)

References 32 publications

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“…Thus, the docking scores could be used potentially in the prediction of cytotoxicity of cardiac glycosides if they exert their bioactivity by targeting NKA directly. Additionally, it is worth noting that compound 9 showed the smallest docking scores (−11.8/−12.9 kcal/mol) and the most potent cytotoxicity against HeLa cells (IC 50 0.26 μM) [ 23 ], suggesting that this compound could be further modified structurally for the development of NKA-targeted antitumor agents.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 1 and 2 were purchased from Sigma-Aldrich (St. Louis, MO, USA), and compounds 3 – 6 , 10 , and 11 were prepared in the previous work by our group; the cancer cell cytotoxicity and molecular targets were already reported [ 19 , 31 ]. In turn, compounds 7 – 9 were selected from the literature, which also reported their bioactivities [ 23 , 32 , 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…However, digoxin is toxic and has a narrow therapeutic index that may result from its NKA inhibition, and this hinders its use in cancer chemotherapy [ 22 ]. Thus, the current interest in digoxin has switched to its synthetic modifications and its interactions with NKA, as exemplified by a new derivative of digoxin, which has a γ-benzylidene group substituted at the C-17-butenolide, which exhibited more potent cytotoxicity and lower NKA inhibitory activity than digoxin itself [ 23 ]. Interestingly, several analogues of digoxin were found to interact with the NKA isoforms specifically and to modulate NKA selectively [ 24 ], indicating that these synthetic derivatives could target NKA differentially to mediate their cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Ren

Burdette

et al. 2021

Molecules

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Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na+/K+-ATPase. The docking profiles for digoxin and several derivatives and Na+/K+-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na+/K+-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na+/K+-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Ren

Burdette

et al. 2021

Molecules

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“…One of these synthetic digoxin analogues, 21-benzylidene digoxin (21-BD), presented cytotoxic and antiproliferative effects when used on HeLa cancer cells, via inducing apoptosis in those cells, but inhibiting NKA activity just at high micromolar levels 18 , 19 . Subsequently, starting with the structure of digoxin, we synthesised a series of γ-benzylidene derivatives and showed that they have cytotoxic effects on HeLa and RKO cancer cell lines that are independent from the modulation of NKA activity 20 .…”

Section: Introductionmentioning

confidence: 99%

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Pessôa

Alves

Taranto

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner.

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“…Alves et al synthesized digoxin derivatives of butenolide with a benzylidene at C-4 of the lactone ring (Figure 32) [134]. The substituent on the aromatic ring had an influence on the antiproliferative activity, and the 4-(dimethylamino)benzylidene derivative of digoxin ( 85a ) showed the most potent activity on HeLa and colon carcinoma (RKO) cells, as well as human lung fibroblasts (WI-26 VA4) (Table 32).…”

Section: Antitumor and Antiviral Activities Of L-ascorbic Acid Dermentioning

confidence: 99%

Therapeutic Perspective of Vitamin C and Its Derivatives

2019

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L-Ascorbic acid (ASA), vitamin C, is a ubiquitous carbohydrate-like compound that has an essential role in a number of cellular processes, such as collagen synthesis, cellular oxidation, and various hydroxylation reactions. ASA is a biomolecule of critical importance for protection of cellular components against oxidative damage caused by toxic free radicals and other reactive oxygen species (ROS) that are involved in the development of various types of chronic diseases. Vitamin C has a switchover role from being an antioxidant in physiological conditions to a prooxidant under pathologic conditions. Moreover, some l-ascorbic acid derivatives exhibit strong and selective antitumor and antiviral activity. This review emphasizes the advances on diverse and potent biological profiles of l-ascorbic acid and its derivatives, and their perspective in the development of new bioactive chemical entities in the future. The work is primarily addressed at antioxidant, anticancer, and antiviral potencies of l-ascorbic acid and compounds containing its butenolide structural motif.

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γ-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect

Cited by 15 publications

References 32 publications

Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Therapeutic Perspective of Vitamin C and Its Derivatives

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