Discovery of N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma

Maccallini, Cristina; Matteo, Mauro Di; Gallorini, M.; Montagnani, Monica; Graziani, Valentina; Ammazzalorso, Alessandra; Amoia, Pasquale; Filippis, Barbara De; Silvestre, Sara Di; Fantacuzzi, Marialuigia; Giampietro, Letizia; Potenza, Maria Assunta; Re, Nazzareno; Pandolfi, Assunta; Cataldi, Amelia; Amoroso, Rosa

doi:10.1016/j.ejmech.2018.04.027

Cited by 20 publications

(29 citation statements)

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“…Results from experiments that aimed to investigate the effect of the NO chemical donor SNAP also support a functional role for NO in the glioma cell survival and proliferation rates as well as clonogenic potential. In addition, the methodological approaches used in this work to study proliferation and migration, together with those aimed at verifying the tumor potential of developing spheres, appear useful for the screening of new and increasingly specific NOS2 inhibitors such as acetamidines, which have been recently discovered and are structurally related to the 1400W [ 31 ]. In this context, our findings could represent a useful contribution to the development of potential therapeutic approaches for the treatment of glioma based on knowledge of the signaling pathways involved in the NO-mediated glioma cell regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacokinetic studies showed that 1400W is an irreversible or an extremely slowly reversible inhibitor of NOS2, although it has been reported to be active for a few hours after administration [ 32 , 33 ]. In the continuous effort to develop even more selective and effective NOS2 inhibitors, different acetamidines structurally related to the 1400W leading scaffold have been published [ 31 , 34 , 35 , 36 , 37 ], thus confirming the growing interest in the pharmacologic potential of NOS2 activity inhibition in different diseases, including GBM.…”

Section: Introductionmentioning

confidence: 99%

“…A major class of NOS2 inhibitors are amidine derivatives, such as L-NIL, the cyclic amidine ONO-1714, and the aromatic acetamidine 1400W [ 29 ]. This latter is considered to be one of the most potent and selective NOS2 inhibitors reported to date [ 29 , 30 , 31 ], although it has never been approved into clinical use. Pharmacokinetic studies showed that 1400W is an irreversible or an extremely slowly reversible inhibitor of NOS2, although it has been reported to be active for a few hours after administration [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Palumbo

Lombardi

Siragusa

et al. 2018

IJMS

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Aberrant nitric oxide synthase 2 (NOS2) expression has been suggested as an interesting therapeutic target that is being implicated as a component of the molecular profile of several human malignant tumors, including glioblastoma, which is the most aggressive brain tumor with limited therapeutic options and poor prognosis. The aim of the present work was to evaluate the effect of 1400W, a specific NOS2 inhibitor, on human glioma cells in terms of clonogenic potential, proliferation, migration rate, and neurosphere generation ability. NOS2 expression was determined by Western blotting. Nitric oxide (NO) production was measured through nitrite level determination. The trypan blue exclusion test and the plate colony formation assay were performed to evaluate cell proliferation and clonogenic potential. Cell proliferation and migration ability was assessed by the in vitro wound-healing assay. Neurosphere generation in a specific stemcell medium was investigated. NOS2 was confirmed to be expressed in both the glioma cell line and a human glioma primary culture, and overexpressed in relative derived neurospheres. Experiments that aimed to evaluate the influence of 1400W on U-87 MG, T98G (glioblastoma cell lines) and primary glioma cells sustained the crucial role played by NOS2 in proliferation, colony formation, migration, and neurosphere generation, thus supporting the emerging relevance of a NOS2/NO system as a prognostic factor for glioma malignancy and recurrence.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Palumbo

Lombardi

Siragusa

et al. 2018

IJMS

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“…Almost simultaneously, the acetamidine derivative N ‐{3‐[(ethanimidoylamino)methyl]benzyl}‐ l ‐prolinamide dihydrochloride (CM544, Figure ) was reported as a potent iNOS inhibitor (IC 50 =0.056 μM) with an improved selectivity profile with respect to 1400 W. This molecule, bearing a proline moiety linked to the 1400 W leading scaffold, showed antiproliferative and cytotoxic effects against C6 rat glioma cells . Interestingly, it did not impair astrocytes viability at the same concentration range, suggesting an important cell selectivity.…”

Section: Small Molecules Able To Downregulate Inos As Antiglioma Agentsmentioning

confidence: 99%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

Self Cite

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Gliomas are the most prevalent primary tumors of the brain and spinal cord. Histologically, they share features of normal glial cells, but whether gliomas originate from normal glial cells, glial or neural precursors, stem cells, or other cell types remains a topic of investigation. The enhanced expression of inducible nitric oxide synthase (iNOS) has been reported as a hallmark of chemoresistance in gliomas, and several lines of evidence have reported that a decreased proliferation of glioma cells could be related to the selective inhibition of iNOS. This review aims to summarize the current understanding of iNOS expression and activity modulation in the regulation of glioma pathogenesis, along with compounds that could act as therapeutic agents against glioma.

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“…It also showed antiproliferative and cytotoxic effects on C6 rat glioma cells. A docking study into iNOS (PDB 1QW5) active site, showed that the acetamidine moiety of compound 114 interacts with Glu and Trp residues of the binding site, the amide –NH group interacts with one heme propionate arm, and the proline amino group binds through a hydrogen bond with the remaining propionate arm . Another mechanistic study on 114 implied that it reduces glioma cell proliferation by increasing the cleavage of PARP‐1 …”

Section: Synthetic Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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Discovery of N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma

Cited by 20 publications

References 27 publications

Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Inducible nitric oxide synthase inhibitors: A comprehensive update

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