Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition

Hill, Timothy A.; Stewart, Scott G.; Gordon, Christopher P.; Ackland, Stephen P.; Gilbert, Jayne; Sauer, Benjamin; Sakoff, Jennette A.; McCluskey, Adam

doi:10.1002/cmdc.200800192

Cited by 65 publications

(47 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8,21,22 PP2B, also known as CaN, is the only Ca 2 þ and calmodulin-dependent Ser/Thr protein phosphatase ubiquitously expressed and is highly conserved in eukaryotes. CaN consists of two subunits: the enzymatic subunit A (CaN A) and the regulatory subunit B (CaN B).…”

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

“…(3) It has been reported that NCTD inhibited not only PP2B but also PP1 and PP2A. 8,22 CsA, however, forms complexes with immunophilins that exert their selective inhibitory action on PP2B. PP1, PP2A, and PP2B all belong to the PPP family of Ser/Thr protein phosphatases and participate in regulating many important physiological processes, such as glycogen metabolism, cell apoptosis, and gene transcription.…”

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

See 1 more Smart Citation

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

Norcantharidin (NCTD) was shown in our previous studies to attenuate renal tubulointerstitial fibrosis in rat models with diabetic nephropathy (DN). The aim of this study was to determine the effects of NCTD on the expression of extracellular matrix (ECM) and TGF-b1 in HK-2 cells stimulated by high glucose and on calcineurin (CaN)/NFAT pathway. Whether or not the antifibrotic effect of NCTD on renal interstitium was dependent on its inhibition of CaN pathway was also investigated. Experimental concentrations of NCTD were verified by cytotoxic test and MTT assay. HK-2 cells were transfected with CaN small interference RNA (siRNA). The mRNA and protein expressions of FN, ColIV, TGF-b1, and CaN in HK-2 cells were detected by real-time PCR and western blot. The CaN/NFAT pathway was examined by indirect immunofluorescence and western blot. Our study revealed that NCTD concentrations over 5 mg/l had overt cytotoxicity on HK-2 cells. Meanwhile, both 2.5 and 5 mg/l NCTD inhibited HK-2 cell proliferation (Po0.05). NCTD inhibited the upregulation of FN, ColIV, and TGF-b1 of HK-2 cells stimulated by high glucose (Po0.05), and also significantly downregulated the expression of CaN mRNA and protein in HK-2 cells (Po0.05). In addition, not only was the nuclear translocation of NFATc inhibited, but its protein level in the nucleus was also reduced. Following CaN siRNA transfection, CaN mRNA and protein expression were significantly decreased. In contrast, the protein levels of FN, ColIV, and TGF-b1 increased in HK-2 cells stimulated by high glucose (Po0.05). However, NCTD treatment downregulated their expression. These results indicated that NCTD could decrease the expression of ECM and TGF-b1 in HK-2 cells stimulated by high glucose, downregulate CaN expression, and block the CaN/NFAT signaling pathway. However, the effect of NCTD on inhibition of the expression of ECM and TGF-b1 was not associated with its inhibition of the CaN/NFAT pathway.

show abstract

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

Section: Effects Of Can Sirna On Can Mrna and Protein Expression Of Hmentioning

confidence: 99%

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Chen

Liu

et al. 2011

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…As shown in Scheme 1, the target compounds II were synthesized by the aminolysis reaction of NCTD I and various halogen aromatic amines in the presence of triethylamine as the binding acid agent, and synthesized via decomposing the anhydride ring of NCTD I by a halogenated aniline with different electronegativity [28].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents

et al. 2015

View full text Add to dashboard Cite

Based on the structure of naturally produced cantharidin, different arylamine groups were linked to the norcantharidin scaffold to provide thirty six compounds. Their structures were confirmed by melting point, 1 H-NMR, 13 C-NMR and HRMS-ESI studies. These synthetic compounds were tested as fungistatic agents against eight phytopathogenic fungi using the mycelium growth rate method. Of these thirty six derivatives, seven displayed stronger antifungal activity than did norcantharidin, seven showed higher activity than did cantharidin and three exhibited more significant activity than that of thiabendazole. In particular, 3-(3 1 -chloro-phenyl)carbamoyl norcantharidate II-8 showed the most significant fungicidal activity against Sclerotinia fructigena and S. sclerotiorum, with IC 50 values of 0.88 and 0.97 µg/mL, respectively. The preliminary structure-activity relationship data of these compounds revealed that: (1) the benzene ring is critical for the improvement of the spectrum of antifungal activity (3-phenylcarbamoyl norcantharidate II-1 vs norcantharidin and cantharidin); (2) among the three sites, including the C-2 1 , C-3 1 and C-4 1 positions of the phenyl ring, the presence of a halogen atom at the C-3 1 position of the benzene ring caused the most significant increase in antifungal activity; (3) compounds with strongly electron-drawing or electron-donating groups substitutions were found to have a poor antifungal activity; and (4) compared with fluorine, bromine and iodine, chlorine substituted at the C-3 1 position of the benzene ring most greatly promoted fungistatic activity. Thus, compound II-8 has emerged as new lead structure for the development of new fungicides.

show abstract

“…Significant effort has been devoted to synthesizing norcantharidin analogs with low toxicity for development as selective phosphatase inhibitor drugs (McCluskey et al, 2000;Hill et al, 2007aHill et al, ,b, 2008. These studies have generated numerous compounds, including the most potent PP2A-and PP1-selective analogs described to date, which have 5-to 15-fold greater potency for growth inhibition (GI 50 ϳ9.6 and ϳ3.3 M, respectively) in several human cancer cell lines compared with norcantharidin (GI 50 ϳ45 M) (Hill et al, 2007b).…”

Section: Pp2a/pp1 Catalytic Subunits As Drug Targetsmentioning

confidence: 99%

Targeting Protein Serine/Threonine Phosphatases for Drug Development

McConnell

Wadzinski

2009

Molecular Pharmacology

158

106

View full text Add to dashboard Cite

With the recent clinical success of drugs targeting protein kinase activity, drug discovery efforts are focusing on the role of reversible protein phosphorylation in disease states. The activity of protein phosphatases, enzymes that oppose protein kinases, can also be manipulated to alter cellular signaling for therapeutic benefits. In this review, we present protein serine/ threonine phosphatases as viable therapeutic targets, discussing past successes, current challenges, and future strategies for modulating phosphatase activity.Numerous cellular processes, including metabolism, immune response, synaptic plasticity, cell growth and proliferation, and apoptosis, are controlled by intricate signal transduction networks composed of molecules and macromolecular protein complexes that are responsive to biological or chemical stimuli in the cell's immediate environment. A common mechanism used by cells to either propagate or terminate intracellular signal transduction pathways is reversible protein phosphorylation, whereby the addition or removal of a negatively charged phosphate can alter the conformation of a target protein and/or its interactions with other proteins. Ultimately, phosphorylation/dephosphorylation reactions affect the activity, function, half-life, or subcellular localization of the substrate; hence, the underlying molecular mechanisms controlling this reversible post-translational modification are of great physiological importance.Careful study has been afforded to the structure, function, and regulation of the enzymes that catalyze phosphorylation or dephosphorylation reactions-protein kinases and phosphatases, respectively. It is widely accepted that proper spatial and temporal regulation of both protein kinases and phosphatases is crucial for maintaining the appropriate balance of phosphorylation required for cellular homeostasis (Bauman and Scott, 2002). Because deregulation of these enzymes has been implicated in a variety of diseases (e.g., cancer, diabetes, cardiac hypertrophy, and neurodegeneration), emerging therapeutic strategies have focused on the design of drugs that affect the biological actions of kinases and phosphatases.Protein kinases have become increasingly popular drug targets, constituting ϳ30% of several pharmaceutical manufacturers' drug discovery programs (Cohen, 2002a). The approval of rapamycin (Sirolimus) for immunosuppression,

show abstract

Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition

Cited by 65 publications

References 38 publications

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Norcantharidin inhibits the expression of extracellular matrix and TGF-β1 in HK-2 cells induced by high glucose independent of calcineurin signal pathway

Synthesis and Biological Evaluation of Norcantharidin Derivatives Possessing an Aromatic Amine Moiety as Antifungal Agents

Targeting Protein Serine/Threonine Phosphatases for Drug Development

Contact Info

Product

Resources

About