5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity

Carmi, Caterina; Cavazzoni, Andrea; Zuliani, Valentina; Lodola, Alessio; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Alfieri, Roberta; Petronini, Pier Giorgio; Mor, Marco

doi:10.1016/j.bmcl.2006.05.010

Cited by 81 publications

(39 citation statements)

References 13 publications

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“…15 Some 1-phenethyl and 5-(E)-benzylidene hydantoins inhibited EGFR autophosphorylation and polyGAT phosphorylation and were found to inhibit the growth and proliferation of human A-431 cells. 16 Therefore, these hydantoins were considered good scaffolds for future design of tyrosine kinase inhibitors. 16 Limited sustainable supply of most bioactive natural products is the main obstacle that may hinder further development as drug leads.…”

Section: Introductionmentioning

confidence: 99%

“…16 Therefore, these hydantoins were considered good scaffolds for future design of tyrosine kinase inhibitors. 16 Limited sustainable supply of most bioactive natural products is the main obstacle that may hinder further development as drug leads. [17][18][19] Feasible regioselective and cost effective synthesis of the pharmacologically active marine natural product 1 not only secured adequate supply for in vitro and animal studies but it also allowed the synthesis of several related analogs for the structureactivity relationship study.…”

Section: Introductionmentioning

confidence: 99%

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Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

Mudit

Khanfar

Anbalagan

et al. 2009

Bioorganic & Medicinal Chemistry

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General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. a b s t r a c tThe Red Sea sponge Hemimycale arabica afforded the known (Z)-5-(4-hydroxybenzylidene)-hydantoin (1), (R)-5-(4-hydroxybenzyl)hydantoin (2), and (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-hydantoin (3). The natural phenylmethylene hydantoin (PMH) 1 and the synthetic (Z)-5-(4-(ethylthio)benzylidene)-hydantoin (4) showed potent in vitro anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT and spheroid disaggregation assays. PMHs 1 and 4 also showed significant anti-invasive activities in orthotopic xenograft and transgenic mice models. To study the effect of electronic and lipophilic parameters on the activity, a wide array of several substituted aldehydes possessing electron-withdrawing (+r), lipophilic (+p), electron-donating (Àr), and less lipophilic substituents (Àp) were used to synthesize several PMHs. Few des-phenylmethylenehydantoins and 2-thiohydanoins were also synthesized and the anti-invasive activities of all compounds were evaluated. Comparative molecular field analysis (CoMFA) was then used to study the 3D QSAR. Predictive 3D QSAR model with conventional r 2 and cross validated coefficient (q 2 ) values up to 0.910 and 0.651 were established. In conclusion, PMH is a novel antimetastatic lead class with potential to control metastatic prostate cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

Mudit

Khanfar

Anbalagan

et al. 2009

Bioorganic & Medicinal Chemistry

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“…Due to their diverse biological and pharmacological properties, hydantoins have been used in a wide variety of therapeutic applications [1]. In particular, hydantoins substituted at the 5-position have been widely used as antiarrhythmic [2], anticonvulsant [3] and antitumoral agents [4]. Closely related analogues of hydantoins are thiohydantoins, which may have one or both of the carbonyl groups replaced by the thiocarbonyl groups.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and crystal structure of (S)-5-isopropyl-5-methyl-2-thiohydantoin

et al. 2013

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KEYWORDS(S)-5-Isopropyl-5-methyl-2-thiohydantoin was synthesized by one-pot reaction of α-methyl-Lvaline and thiourea in the absence of solvent. The crystal structure of this compound has been determined from single crystal X-ray diffraction data. This is the first report on the crystal structure of a homochiral 5-substituted 2-thiohydantoin with the unsubstituted NH groups. This compound, C7H12N2OS crystallizes in the chiral orthorhombic space group P212121 with four molecules in the unit cell. The unit cell parameters are: a = 8.2798(12) Å, b = 8.6024(13) Å, c = 12.826(2) Å and V = 913.6(2) Å 3 . In the crystals, the thioamide and amide N-H of one molecule are hydrogen-bonded to the thioamide C=S group of neighboring molecules to form rings with the R 2 2(8) graph-set motif, and these rings are linked into infinite one-dimensional tapes.Thiourea Homochiral Hydrogen-bond Crystal structure 2-Thiohydantoin 2-Thioxoimidazolidin-4-one

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“…Where, some 1-phenethyl-5-(E)-benzylidine hydantoins 4 inhibited EGFR autophosphorylation and polyglutamic acid/ tyrosine (polyGAT) phosphorylation. 18,19) Moreover, a series of hydrazono thiazolidin-4-one 5 that own high antineoplastic activity against breast cancer cells MCF-7 and were potent inhibitors of EGFR autophosphorylation has been repoted. 20) Furthermore, dianilinophthalimide 6 that can bind competitively with the ATP to EGFR showed good selectivity between different tyrosine kinases.…”

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confidence: 99%

Novel Diphenylamine 2,4'-Dicarboxamide Based Azoles as Potential Epidermal Growth Factor Receptor Inhibitors: Synthesis and Biological Activity

Abou‐Seri

Farag

Hassan

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Breast cancer is the second leading cause of cancer deaths in women today and is the most common cancer among women, excluding nonmelanoma skin cancers.1) Despite the progress achieved in anticancer therapy about 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465000 will die from the disease.1) Accordingly, novel therapeutic strategies to improve prognosis are urgently needed.It is increasingly apparent that a number of protein tyrosine kinases, specifically epidermal growth factor receptor (EGFR) tyrosine kinase and/or its family members play a critical role in the development and progression of many solid tumors, including breast cancer.2,3) Over-expression of EGFR has been observed in about 70% of breast cancer 4) and is associated with later stages of carcinogenesis 5,6) and is implicated in the development of drug resistance with poor prognosis.7-9) Therefore inhibitors of EGFR kinase activity have emerged as promising new approach to cancer therapy.During the last decade azolidinones heterocycles, particularly imidazolidinones, thiazolidinones and pyrrolidinone have gained special attention as potential lead compounds for novel anticancer agents.10) The antineoplastic properties of azolidinones and related heterocycles are most probably caused by their affinity to different anticancer biotargets, such as extracellular signal-regulated kinases (ERK kinases), 11,12) JNK-stimulating phosphatase-1 (JSP-1) 1, 13) tumor necrosis factor-alpha (TNF-a), 14,15) antiapoptic complex Bcl-X L -BH3 2, 16) integrin a v b 3 receptor 3, 17) etc. (Fig. 1). Recent reports showed that imidazolidinones, and thiazolidinones were found to inhibit the kinase activity of EGFR. Where, some 1-phenethyl-5-(E)-benzylidine hydantoins 4 inhibited EGFR autophosphorylation and polyglutamic acid/ tyrosine (polyGAT) phosphorylation. 18,19) Moreover, a series of hydrazono thiazolidin-4-one 5 that own high antineoplastic activity against breast cancer cells MCF-7 and were potent inhibitors of EGFR autophosphorylation has been repoted. 20) Furthermore, dianilinophthalimide 6 that can bind competitively with the ATP to EGFR showed good selectivity between different tyrosine kinases.21) Therefore, azolidinones are considered good scaffolds for future design of tyrosine kinase inhibitors. In addition, benzamides and bezamidines were synthesized as mimics of the classical EGFR inhibitors 4-anilino-quinazolines.22) Also, we have recently reported preliminary results on antiproliferative action of 2,4Ј-bis-heterocyclic diphenylamine 7 against MCF-7 cell line, that might be mediated through the inhibition EGFR kinase activity. 23)Promoted by these observations and in continuation to the previous work, 23) we designed and synthesized hybrid molecules of diphenylamine-2,4Ј-dicarboxamide (as dibenzamide template) and different azolidinones or related heterocyclic rings 11, 13-17 aiming to obtain highly active antitumor agents, with probable EGFR tyrosine kinase inhibitory activity. The new hybrids were inspired by co...

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5-Benzylidene-hydantoins as new EGFR inhibitors with antiproliferative activity

Cited by 81 publications

References 13 publications

Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

Synthesis and crystal structure of (S)-5-isopropyl-5-methyl-2-thiohydantoin

Novel Diphenylamine 2,4'-Dicarboxamide Based Azoles as Potential Epidermal Growth Factor Receptor Inhibitors: Synthesis and Biological Activity

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