Structure–activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation

Zhou, Huchen; Wang, De An; Baldini, Laura; Ennis, Eileen; Jain, Rishi K.; Carie, Adam; Sebti, Saı̈d M.; Hamilton, Andrew D.

doi:10.1039/b515483a

Cited by 46 publications

(36 citation statements)

References 40 publications

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“…Such an interaction has been previously demonstrated for similar compounds built on a calixarene scaffold and exhibiting anticancer activity [7,8,21] . The mechanism underlying the interaction between compounds 1 and 2 and growth factors remains to be determined, but we were here able to show that it relies on a portion of the molecule different from the GlcNAs moieties and rather related to the presence of the ureido groups.…”

Section: Discussionmentioning

confidence: 92%

Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes

Viola

Merlo²,

Consoli³

et al. 2010

Pharmacology

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Calixarenes are synthetic macrocyclic compounds that may serve as scaffolds for biologically active molecules and have been proposed as potential anticancer agents. We synthesized a ureido-calix[8]arene carrying N-acetyl-D-glucosamine residue (compound 1) and had previously demonstrated that it inhibits C6 glioma cell migration and proliferation, with divergent mechanisms. In the present work we explored in more detail the antiproliferative effect of compound 1, comparing it to related compounds lacking either the sugar moieties (compound 2), the multiple ureido groups (compound 3) or both (compound 4). The results show that the action of compound 1 is independent of the N-acetyl-D-glucosamine residues, requires the presence of multiple ureido groups and does not seem to involve focal adhesion kinase signaling. Inhibition of proliferation is reduced by preincubation with epidermal growth factor (EGF) and vascular endothelial growth factor (20 ng/ml) with compound 1, and extracellular-related kinase phosphorylation is reduced by treatment with compound 1 in both basal and EGF-stimulated conditions, suggesting that the observed effect depends on a direct interference with growth factor signaling.

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Section: Discussionmentioning

confidence: 92%

Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes

Viola

Merlo²,

Consoli³

et al. 2010

Pharmacology

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“…The Glide program (Schrodinger) was used to screen the Specs database consisting of 197,000 compounds. The fluorescence of tryptophan was measured as described by Zhou et al (42). The computation methods, compound synthesis, determination of in vitro ZCL278-Cdc42 binding affinity by fluorescence titration and SPR, determination of protein distribution and expression, are detailed in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

Friesland

Zhao

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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153

148

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Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42–ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.

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“…Although the impact of these processes is known for the development of Kaposi’s sarcoma, the effect of these growth factors and receptors on HIV replication itself is still under investigation. The discovery of calix[4]arene derivatives that block VEGF and PDGF with their respective receptors7–10 provided an opportunity to investigate the effect of this compound series on the replication of HIV. Moreover, a number of studies have shown that certain calixarene derivatives have interesting activities against viruses, enveloped viruses, bacteria, fungi, and cancerous cells 11.…”

mentioning

confidence: 99%

Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold

Tsou

Dutschman

Gullen

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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A potential anti-HIV and HCV drug candidate is highly desirable as coinfection has become a worldwide public health challenge. A potent compound based on a tetrabutoxy-calix [4]arene scaffold that possesses dual inhibition for both HIV and is described. Structural activity relationship studies demonstrate the effects of lower-rim alkylation in maintaining cone conformation and upper-rim interating head groups on the calix[4]arene play key roles for its potent dual antivial activities.Coinfection with both human immunodeficiency virus 1 (HIV) and hepatitis C virus (HCV) has become a public health challenge, afflicting more than ten million people worldwide.1 , 2 Complicating the challenge is the realization that with the advancement in highly active antiretroviral therapy (HAART), liver disease has emerged as a leading cause of death among HIVinfected patients.3 Treatment of coinfected patients with HAART has resulted in more liver toxicity4, creating a major health problem as there is currently no specific anti-HCV drug available. Therefore, the discovery of a dual compound as a potential drug candidate that can block HIV and HCV infection would be desirable. Herein, we report the first synthetic dual inhibitor of HIV and HCV infection in vitro based on a new class of compounds derived from a tetrabutoxy-calix[4]arene scaffold.The secretion of vascular endothelial growth factor (VEGF) is elevated in HIV infected T-cells and is a major factor in the development of Kaposi's sarcoma.5 In addition, platelet derived growth factor receptor (PDGFR) is expressed by uninfected T-cell lines, in which secretion of PDGF is also observed6. Although the impact of these processes is known for the development of Kaposi's sarcoma, the effect of these growth factors and receptors on HIV replication itself is still under investigation. The discovery of calix [4]arene derivatives that block VEGF and PDGF with their respective receptors7 -10 provided an opportunity to investigate the effect of this compound series on the replication of HIV. Moreover, a number of studies have shown that certain calixarene derivatives have interesting activities against viruses, enveloped viruses, bacteria, fungi, and cancerous cells.11 In these reports12 ,13 , the macrocyclic scaffolds are based on pyrogallol calixarenes, calixarenes and resorcarenes of different ring sizes (4, 6, and 8 units) without functionality at the lower rim and with sulfite, phosphite or simple carboxylic

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Structure–activity studies on a library of potent calix[4]arene-based PDGF antagonists that inhibit PDGF-stimulated PDGFR tyrosine phosphorylation

Cited by 46 publications

References 40 publications

Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes

Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

Discovery of a synthetic dual inhibitor of HIV and HCV infection based on a tetrabutoxy-calix[4]arene scaffold

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