An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512

Palermo, Giulia; Minniti, Elirosa; Greco, Maria Laura; Riccardi, Laura; Simoni, Elena; Convertino, Marino; Marchetti, Chiara; Rosini, Michela; Sissi, Claudia; Minarini, Anna; Vivo, Marco De

doi:10.1039/c5cc05065k

Cited by 33 publications

(43 citation statements)

References 28 publications

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“…Milelli et al developed a series of polyamine‐based hybrid compounds, from which emerged 115 (Figure ), showing interesting inhibitory activity against LSD1 (IC 50 LSD1‐CoREST3 = 3.8 μM) and HDAC1 (Ki HDAC1‐CoREST3 = 42.5 nM) in vitro as well as in cellular assays. In 115 , the two anti‐HDAC and ‐LSD1 pharmacophoric portions were connected using a polyamine‐type chain, since the polyamine moiety can interact with both LSD1 and HDAC enzymes due to protonated nitrogen atoms allowing electrostatic interactions with negatively charge amino acid residues . Among the different polyamine linkers used, the spermine (3‐4‐3), typical of 115 , produced the best enzymatic results.…”

Section: The Mtdl Approachmentioning

confidence: 99%

“…and HDAC enzymes [403][404][405] due to protonated nitrogen atoms allowing electrostatic interactions with negatively charge amino acid residues. 406,407 Among the different polyamine linkers used, the spermine (3-4-3), typical of 115, produced the best enzymatic results. When tested against MCF7 breast cancer cell line, 115 resulted more effective (at high concentration) than vorinostat 3 in inducing cytotoxicity (68.6% vs 56.6% of dead cells).…”

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confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Section: The Mtdl Approachmentioning

confidence: 99%

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confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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“…In this respect, much has achieved in terms of free‐energy perturbation (FEP) calculations . We are confident that efficient and easy‐to‐prepare protocols and set‐ups for methods like steered‐MD and metadynamics will soon undergo similar improvements for prospective drug design . This will further open up these methods to computational medicinal chemistry.…”

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confidence: 99%

Recent advances in dynamic docking for drug discovery

Vivo

Cavalli

2017

WIREs Comput Mol Sci

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Molecular docking allows the evaluation of ligand‐target complementarity. This is the crucial first step in small‐molecule drug discovery. Over the last decade, increasing computer power and more efficient molecular dynamics (MD) software have prompted the use of MD for molecular docking. The resulting dynamic docking offers major improvements by (1) taking full account of the structural flexibility of the drug‐target system and (2) allowing the computation of the free energy and kinetics associated with drug binding. Here, we examine the recent advances in dynamic docking, while also considering the challenges and limitations that this powerful approach must overcome to impact fast‐paced drug discovery. WIREs Comput Mol Sci 2017, 7:e1320. doi: 10.1002/wcms.1320 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Mechanics Software > Molecular Modeling

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“…16 These polyamines were chosen because a previous study found that the presence of a secondary amine group in the side chain plays an important role in mediating topoisomerase II-drug interactions. 43–45 Furthermore, the addition of a spermine side chain to the core of etoposide (generating F14512) greatly enhanced the ability of the drug to act as a topoisomerase II poison and to be taken up by cancer cells with active polyamine transport systems. 43–47 …”

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“…58 The polyamine chain extends toward the DNA major groove, as was observed in previous computations of F14512 and other polyamine-conjugates. 45 Compound 4 has the potential to form several favorable interactions with both the enzyme and the DNA. The hydroxyl group along the polyamine chain points toward Gln778, while the central nitrogen atom is in close enough proximity to form hydrogen bonds with the backbone of either Lys814 or Ala816.…”

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Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα

Minniti

Byl

Riccardi

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors. Although xanthone derivatives inhibit topoisomerase IIα-catalyzed ATP hydrolysis, mechanistic studies indicate that they do not act at the ATPase site. Rather, they appear to function by blocking the ability of DNA to stimulate ATP hydrolysis. On the basis of activity, competition, and modeling studies, we propose that xanthones interact with the DNA cleavage/ligation active site of topoisomerase IIα and inhibit the catalytic activity of the enzyme by interfering with the DNA strand passage step.

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An optimized polyamine moiety boosts the potency of human type II topoisomerase poisons as quantified by comparative analysis centered on the clinical candidate F14512

Cited by 33 publications

References 28 publications

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Recent advances in dynamic docking for drug discovery

Novel xanthone-polyamine conjugates as catalytic inhibitors of human topoisomerase IIα

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