Novel analogues of Istaroxime, a potent inhibitor of Na+,K+-ATPase: Synthesis, structure–activity relationship and 3D-quantitative structure–activity relationship of derivatives at position 6 on the androstane scaffold

Gobbini, Mauro; Armaroli, Silvia; Banfi, Leonardo; Benicchio, Alessandra; Carzana, Giulio; Ferrari, Paolo; Giacalone, Giuseppe; Marazzi, Giuseppe; Moro, Barbara; Micheletti, R.

doi:10.1016/j.bmc.2010.04.095

Cited by 15 publications

(17 citation statements)

References 22 publications

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“…Cardiac compounds used in these studies have been synthesized with modifications as previously described [28][29][30][31][32]. Details on their synthesis and characterization are provided in the Supplementary Materials & Methods Section.…”

Section: Methodsmentioning

confidence: 99%

“…The structures of all tested compounds are depicted in Supplementary Table 1. Overall, these include several oximes at the position C3 (R 1 ) of the carbon skeleton in combination with different substitutions at carbons C5, C6, C7 and C17 (R 2 , R 3 , R 4 and R 5 respectively) [28][29][30][31]. Screening of IC 50 inhibitory activities of all compounds, as determined by in vitro Na + /K + ATPase assays using purified porcine brain enzymes, are presented in Supplementary Table 2 ("NaK Assay" column).…”

Section: Compound Structures and Na + /K + Atpase Ic 50 Inhibitory Acmentioning

confidence: 99%

“…To overcome these problems, several groups focused on the development of second generation cardiac Na + /K + ATPase inhibitors with improved therapeutic indices. A promising class of novel, non-sugar containing, steroidal compounds exemplified by clinical phase II cardiac drug istaroxime was consequently described and tested in various preclinical and clinical trials with promising results [28][29][30][31][32]. However, the potential anti-cancer activity of these compounds remained unknown to date as these compounds were exclusively developed and tested for cardiac indications.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we have synthesized, characterized and tested for the first time 17 steroidal Na + /K + ATPase cardiac inhibitors [28][29][30][31] for their anti-cancer activity in vitro. Istaroxime was also included in all our experiments; corresponding results will be presented in a separate publication (manuscript in preparation).…”

Section: Introductionmentioning

confidence: 99%

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Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Dimas¹,

Papadopoulou²,

Baskakis³

et al. 2014

ACAMC

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Sodium potassium pump (Na(+)/K(+)ATPase) is a validated pharmacological target for the treatment of congestive heart failure. Recent data with inotropic drugs such as digoxin & digitoxin (digitalis) suggest a potent anti-cancer action of these drugs and promote Na(+)/K(+)ATPase as a novel therapeutic target in cancer. However, digitalis have narrow therapeutic indices, are pro-arrhythmic and are considered non-developable drugs by the pharmaceutical industry. On the contrary, a series of recently-developed steroidal inhibitors showed better pharmacological properties and clinical activities in cardiac patients. Their anti-cancer activity however, remained unknown. In this study, we synthesized seventeen steroidal cardiac inhibitors and explored for the first time their anti-cancer activity in vitro and in vivo. Our results indicate potent anti-cancer actions of steroidal cardiac inhibitors in multiple cell lines from different tumor panels including multi-drug resistant cells. Furthermore, the most potent compound identified in our studies, the 3-[(R)-3- pyrrolidinyl]oxime derivative 3, showed outstanding potencies (as measured by GI50, TGI and LC50 values) in most cells in vitro, was selectively cytotoxic in cancer versus normal cells showing a therapeutic index of 31.7 and exhibited significant tumor growth inhibition in prostate and lung xenografts in vivo. Collectively, our results suggest that previously described cardiac Na(+)/K(+)ATPase inhibitors have potent anti-cancer actions and may thus constitute strong re-purposing candidates for further cancer drug development.

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Section: Methodsmentioning

confidence: 99%

Section: Compound Structures and Na + /K + Atpase Ic 50 Inhibitory Acmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Steroidal Cardiac Na+/K+ ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Dimas¹,

Papadopoulou²,

Baskakis³

et al. 2014

ACAMC

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“…Searching for these molecules has yielded istaroxime analogs with better activity, and even structure-activity relationships have been found. 45,46 Further, a high-throughput fluorescence resonance energy transfer assay has been used to find allosteric SERCA2a activators capable of decreasing SERCA2a/PLN-derived fluorescence resonance energy transfer. 47 In this study, several compounds previously reported to correct aberrant Ca 2+ regulation in HF were shown to activate SERCA2a activity, thus validating the mechanism of action for these drugs.…”

mentioning

confidence: 99%

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Fragoso-Medina¹,

Zarain‐Herzberg²

2014

RRCC

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Abstract:The complexity of heart physiology has delayed the implementation of efficient, feasible, and safe therapies to fight against heart diseases for many years. As knowledge of the precise mechanisms governing cardiac hypertrophy and heart failure development increases, the availability of new therapeutic alternatives also grows. Since the cardiomyocyte physiology deeply depends on the correct calcium handling, many efforts to describe accurately the excitation-contraction coupling process in the heart and the proteins involved have been made. Among the proteins participating in calcium handling, sarco/endoplasmic reticulum Ca 2+ adenosine triphosphatase-2a (SERCA2a), whose expression and function is decreased in heart failure, stands out because of its critical role regulating Ca 2+ concentration in the cardiomyocyte. The importance of SERCA2a has been reflected in numerous studies aimed to describe its expression and function. Recently, gene therapy to deliver SERCA2a has shown promising results in human clinical trials. This paper reviews the current literature knowledge exploring diverse approaches to rescue SERCA2a expression in heart failure. It also discusses some data suggesting other possible therapies that could improve SERCA2a expression and function in cardiac diseases.

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Treatments for Heart Failure

Seganish

Lynch

Sorota

2017

Comprehensive Medicinal Chemistry III

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Novel analogues of Istaroxime, a potent inhibitor of Na+,K+-ATPase: Synthesis, structure–activity relationship and 3D-quantitative structure–activity relationship of derivatives at position 6 on the androstane scaffold

Cited by 15 publications

References 22 publications

Steroidal Cardiac Na<sup>+</sup>/K<sup>+</sup> ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

Steroidal Cardiac Na<sup>+</sup>/K<sup>+</sup> ATPase Inhibitors Exhibit Strong Anti-Cancer Potential in vitro and in Prostate and Lung Cancer Xenografts in vivo

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Treatments for Heart Failure

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