Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds

Bordessa, Andrea; Colin, Christelle; Grillier-Vuissoz, Isabelle; Kuntz, Sandra; Mazerbourg, Sabine; Husson, Gauthier; Vo, Myriam; Flament, Stéphane; Martin, Hélène; Chapleur, Yves; Boisbrun, Michel

doi:10.1016/j.ejmech.2014.06.015

Cited by 28 publications

(40 citation statements)

References 32 publications

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“…Due to adverse events this drug was withdrawn from the market in 2000. Yet, new troglitazone derivatives with lower toxicity and anti-proliferative activity are now emerging (48). Two other compounds, econazole nitrate and promazine hydrochloride, showed synergy in the SUDHL6 cell line.…”

Section: Discussionmentioning

confidence: 99%

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression

et al. 2016

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Follicular lymphoma (FL), the most common indolent subtype of non-Hodgkin’s lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from time of diagnosis. However, in 20–60% of FL patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of FL transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of FL transformation, we performed systematic analysis of a B-cell-specific regulatory model exhibiting FL transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to FL transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression

et al. 2016

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“…Regarding tocopherol analogues, several tocopherolthiazolidinedione hybrid compounds have been shown to possess anticancer properties in vitro and in vivo. Particularly, troglitazone (Figure 1) presented antiproliferative activity in several cancer cell lines [13,14]. On the other hand, hybrid molecules combining tocopherol derivatives and nitric oxide releasing moieties ( .…”

Section: Introductionmentioning

confidence: 99%

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

Ingold

Dapueto

Victoria

et al. 2018

European Journal of Medicinal Chemistry

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A one-pot efficient, practical and eco-friendly synthesis of tocopherol analogues has been developed using water or solvent free conditions via Passerini and Ugi multicomponent reactions. These reactions can be optimized using microwave irradiation or ultrasound as the energy source. Accordingly, a small library of 30 compounds was prepared for biological tests. The evaluation of the antiproliferative activity in the human solid tumor cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast), and WiDr (colon) provided lead compounds with GI values between 1 and 5 μM. A structure-activity relationship is also discussed. One of the studied compounds comes up as a future candidate for the development of potent tocopherol-mimetic therapeutic agents for cancer.

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“…This information has recently been used by Bordessa et al. for the design and synthesis of Troglitazone derivatives towards the development of more active and safer anti‐proliferative agents . Toxicity of thiophene containing drugs was explored by Jaladanki et al .…”

Section: Substrate Specific Studies To Understand Cyp450 Catalyzed Dmentioning

confidence: 99%

Advances in Computational Prediction of Regioselective and Isoform-Specific Drug Metabolism Catalyzed by CYP450s.

Dixit

Deshpande

2016

ChemistrySelect

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Prediction of drug metabolism is an important step in the early lead optimization phase and preclinical studies. Its main purpose is to avoid late stage (Phase I–III) or post‐marketing withdrawals which usually results in a significant financial loss to a pharmaceutical company. Computational methods for identification of soft‐spots in the molecules (site of metabolism; SOM) and CYP450 isoforms responsible for drug metabolism have over the past ten years proved an indispensable tool towards achieving this goal. These methods can be broadly classified into i) ligand based, ii) structure based and iii) hybrid methods. In this review we discuss some of the most successful methods of SOM and isoform specificity prediction, their application domain, advantages, and limitations along with recent developments in the last 5 years in this area. Recent applications of molecular dynamics (MD), quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) methodology for regioselective and isoform specific drug metabolism predictions are also discussed. Finally, a summary of these methods along with expected developments, future challenges and opportunities are discussed.

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Optimization of troglitazone derivatives as potent anti-proliferative agents: Towards more active and less toxic compounds

Cited by 28 publications

References 32 publications

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression

A green multicomponent synthesis of tocopherol analogues with antiproliferative activities

Advances in Computational Prediction of Regioselective and Isoform-Specific Drug Metabolism Catalyzed by CYP450s.

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