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Synthesis, characterization, and evaluation of a novel inhibitor of WNT/β-catenin signaling pathway.

Yan Z, Zhu Z, Wang J, Sun J, Chen Y, Yang G, Chen W, Deng Y - Mol. Cancer (2013)

Bottom Line: The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment.The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model.Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P, R, China. yanzhaotj@126.com.

ABSTRACT

Background: Wnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo.

Results: Cell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43 ± 1.99, 6.95 ± 0.24, and 7.62 ± 1.31 μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100 mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound.

Conclusions: Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

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Crystal structure of compound 3. To confirm the regiochemistry of the cycloaddition for Δ2-pyrazoline 3, a single crystal for compound 3 was obtained. The absolute configuration was determined using X-ray structural analysis.
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Figure 2: Crystal structure of compound 3. To confirm the regiochemistry of the cycloaddition for Δ2-pyrazoline 3, a single crystal for compound 3 was obtained. The absolute configuration was determined using X-ray structural analysis.

Mentions: The 1,3-dipolar cycloaddition reaction using nitrilimines is a well-known process[22-28]. This synthesis usually generates the corresponding pyrazolines as a mixture of regioisomers[29-31], but no direct evidence is available to reveal which regioisomers are obtained in this reaction. We prepared nitrilimine 3 by dehydrogenation of aldehyde hydrazine 1 with chloramine-T[32]. In the presence of ethyl cinnamate as dipolarophile, in situ-generated diphenyl nitrilimine 2 yielded the pyrazoline. After hydrolysis of compound 4 and subsequent coupling, we obtained our target compound, BHX (Figure 1). To confirm the regiochemistry of the cycloaddition for ∆2-pyrazoline 3, 1H, 13C-HMQC and 1H, 13C-HMBC experiments were performed. We also obtained a single crystal for compound 3 (Figure 2) to determine the absolute configuration of the cycloadduct by X-ray structural analysis, which was consistent with the results of spectral analysis.


Synthesis, characterization, and evaluation of a novel inhibitor of WNT/β-catenin signaling pathway.

Yan Z, Zhu Z, Wang J, Sun J, Chen Y, Yang G, Chen W, Deng Y - Mol. Cancer (2013)

Crystal structure of compound 3. To confirm the regiochemistry of the cycloaddition for Δ2-pyrazoline 3, a single crystal for compound 3 was obtained. The absolute configuration was determined using X-ray structural analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852836&req=5

Figure 2: Crystal structure of compound 3. To confirm the regiochemistry of the cycloaddition for Δ2-pyrazoline 3, a single crystal for compound 3 was obtained. The absolute configuration was determined using X-ray structural analysis.
Mentions: The 1,3-dipolar cycloaddition reaction using nitrilimines is a well-known process[22-28]. This synthesis usually generates the corresponding pyrazolines as a mixture of regioisomers[29-31], but no direct evidence is available to reveal which regioisomers are obtained in this reaction. We prepared nitrilimine 3 by dehydrogenation of aldehyde hydrazine 1 with chloramine-T[32]. In the presence of ethyl cinnamate as dipolarophile, in situ-generated diphenyl nitrilimine 2 yielded the pyrazoline. After hydrolysis of compound 4 and subsequent coupling, we obtained our target compound, BHX (Figure 1). To confirm the regiochemistry of the cycloaddition for ∆2-pyrazoline 3, 1H, 13C-HMQC and 1H, 13C-HMBC experiments were performed. We also obtained a single crystal for compound 3 (Figure 2) to determine the absolute configuration of the cycloadduct by X-ray structural analysis, which was consistent with the results of spectral analysis.

Bottom Line: The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment.The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model.Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P, R, China. yanzhaotj@126.com.

ABSTRACT

Background: Wnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo.

Results: Cell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43 ± 1.99, 6.95 ± 0.24, and 7.62 ± 1.31 μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100 mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound.

Conclusions: Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

Show MeSH
Related in: MedlinePlus