Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies

Brindisi, Margherita; Senger, Johanna; Cavella, Caterina; Grillo, Alessandro; Chemi, Giulia; Gemma, Sandra; Cucinella, Dora Mariagrazia; Lamponi, Stefania; Sarno, Federica; Iside, Concetta; Nebbioso, Angela; Novellino, Ettore; Shaik, T.B.; Romier, Christophe; Herp, Daniel; Jung, Manfred; Butini, Stefania; Campiani, Giuseppe; Altucci, Lucia; Brogi, Simone

doi:10.1016/j.ejmech.2018.07.069

Cited by 41 publications

(49 citation statements)

References 81 publications

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“…The other aromatic feature was mapped to the pyridine ring of the nicotinamide moiety. This hypothesis was well corroborated by accepted common pharmacophore model for HDACIs comprising the zinc binding group (ZBG), a linker and a cap group as established by computational and biophysical studies reported for HDAC1 inhibitors [66][67][68][69][70]. Based on the current study, the aniline groups of the benzamide-based inhibitors are served as ZBG, coordinating the catalytic zinc ion in the HDAC1 active site.…”

Section: Pharmacophore Modeling and 3d-qsar Model Generationsupporting

confidence: 77%

“…The presence of two aromatic features capable of participating in π-π stacking interactions with hydrophobic residues Phe150, Tyr204, Phe205, and Tyr303, represents another important requisite for further stabilization of ligand binding. These residues were located in a long and narrow hydrophobic tube-like channel and thus interaction with them allow tubular access of ligand into active site [66,67,69,70]. Accordingly, the above-mentioned ADDRR hypothesis imparts the key features of ligand for providing the relevant interactions with the HDAC1 active site.…”

Section: Pharmacophore Modeling and 3d-qsar Model Generationmentioning

confidence: 99%

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Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

et al. 2020

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Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R 2 = 0.958) and a satisfactory predictive power (Q 2 = 0.822; Q 2 F3 = 0.894). The model was validated (r 2 ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.Molecules 2020, 25, 1952 2 of 20 chromatin structure which concomitantly restricts the accessibility of related transcriptional factors to their target genes, thereby suppressing gene expression including tumor suppressor genes [6][7][8]. The abnormal regulation of this process culminates with the high expression level of HDACs. This event has been observed in the development of several human cancers. Consequently, effective inhibition of HDACs has recently gained importance as a valid therapeutic strategy to reverse aberrant epigenetic changes associated with cancer [9][10][11]. HDAC inhibitors (HDACIs) induce histone hyperacetylation and subsequent transcriptional re-activation of suppressed genes which are correlated with a variety of effects on tumor cells including apoptosis, differentiation, cell cycle arrest, inhibition of proliferation and cytostasis [12,13].The HDAC family comprises 18 isoforms in mammalian cells which are categorized into four main classes (class I-IV) based on their structural and functional characteristics. HDACs belonging to class I (HDAC1-3 and 8), II (HDACs 4-7, 9 and 10) and IV (HDAC11) are all zinc-dependent metalloenzymes, while class III HDACs, also known as the sirtuins (SIRT1-7), requires NAD + as a cofactor for their catalytic function [6,14].Extensive efforts over recent decades have led to the identification of four chemically diverse classes of HDACIs as potent antineoplastic agents including, hydroxamates, benzamides, cyclic peptides, and short-chain fatty acids [3]. The main...

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Section: Pharmacophore Modeling and 3d-qsar Model Generationsupporting

confidence: 77%

Section: Pharmacophore Modeling and 3d-qsar Model Generationmentioning

confidence: 99%

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

et al. 2020

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“…Thus, microtubule PTMs may be a potential target for therapeutic intervention. In this regard, drugs targeting acetylation such as HDAC6 (histone deacetylase 6) inhibitors have been investigated for the treatment of depression, cancer, stroke, environmental stress and Huntington's disease (Dompierre et al, 2007 ; Lazo-Gómez et al, 2013 ; Simoes-Pires et al, 2013 ; Jochems et al, 2014 ; Brindisi et al, 2016 , 2018 ; Ceccacci and Minucci, 2016 ; Wang et al, 2016 ; Rao et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The HDAC6 Inhibitor Trichostatin A Acetylates Microtubules and Protects Axons From Excitotoxin-Induced Degeneration in a Compartmented Culture Model

et al. 2018

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Axon degeneration has been implicated as a pathological process in several neurodegenerative diseases and acquired forms of neural injury. We have previously shown that stabilizing microtubules can protect axons against excitotoxin-induced fragmentation, however, the alterations of microtubules following excitotoxicity that results in axon degeneration are currently unknown. Hence, this study investigated whether excitotoxicity affects the post-translational modifications of microtubules and microtubule-associated proteins, and whether reversing these changes has the potential to rescue axons from degeneration. To investigate microtubule alterations, primary mouse cortical neurons at 10 days in vitro were treated with 10 or 25 μM kainic acid to induce excitotoxicity and axon degeneration. Post-translational modifications of microtubules and associated proteins were examined at 6 h following kainic acid exposure, relative to axon degeneration. While there were no changes to tyrosinated tubulin or MAP1B, acetylated tubulin was significantly (p < 0.05) decreased by 40% at 6 h post-treatment. To determine whether increasing microtubule acetylation prior to kainic acid exposure could prevent axon fragmentation, we investigated the effect of reducing microtubule deacetylation with the HDAC6 inhibitor, trichostatin A. We found that trichostatin A prevented kainic acid-induced microtubule deacetylation and significantly (p < 0.05) protected axons from fragmentation. These data suggest that microtubule acetylation is a potential target for axonal protection where excitotoxicity may play a role in neuronal degeneration.

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“…Then, GO terms were used to annotate and identify immune-related DEGs. Moreover, the human protein–protein interaction (PPI) network analysis was introduced to explore the connection among identified DEGs [99]. In particular, the STRING database [100] was adopted to the construct human PPI network, and only PPI data of high confidence levels (>0.7) were applied in this study.…”

Section: Methodsmentioning

confidence: 99%

Biomarker Discovery for Immunotherapy of Pituitary Adenomas: Enhanced Robustness and Prediction Ability by Modern Computational Tools

Yang

Zhang

Tang

et al. 2019

IJMS

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Pituitary adenoma (PA) is prevalent in the general population. Due to its severe complications and aggressive infiltration into the surrounding brain structure, the effective management of PA is required. Till now, no drug has been approved for treating non-functional PA, and the removal of cancerous cells from the pituitary is still under experimental investigation. Due to its superior specificity and safety profile, immunotherapy stands as one of the most promising strategies for dealing with PA refractory to the standard treatment, and various studies have been carried out to discover immune-related gene markers as target candidates. However, the lists of gene markers identified among different studies are reported to be highly inconsistent because of the greatly limited number of samples analyzed in each study. It is thus essential to substantially enlarge the sample size and comprehensively assess the robustness of the identified immune-related gene markers. Herein, a novel strategy of direct data integration (DDI) was proposed to combine available PA microarray datasets, which significantly enlarged the sample size. First, the robustness of the gene markers identified by DDI strategy was found to be substantially enhanced compared with that of previous studies. Then, the DDI of all reported PA-related microarray datasets were conducted to achieve a comprehensive identification of PA gene markers, and 66 immune-related genes were discovered as target candidates for PA immunotherapy. Finally, based on the analysis of human protein–protein interaction network, some promising target candidates (GAL, LMO4, STAT3, PD-L1, TGFB and TGFBR3) were proposed for PA immunotherapy. The strategy proposed together with the immune-related markers identified in this study provided a useful guidance for the development of novel immunotherapy for PA.

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Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies

Cited by 41 publications

References 81 publications

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

Computer-Driven Development of an in Silico Tool for Finding Selective Histone Deacetylase 1 Inhibitors

The HDAC6 Inhibitor Trichostatin A Acetylates Microtubules and Protects Axons From Excitotoxin-Induced Degeneration in a Compartmented Culture Model

Biomarker Discovery for Immunotherapy of Pituitary Adenomas: Enhanced Robustness and Prediction Ability by Modern Computational Tools

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