Development of pyrazoline-based derivatives as aminopeptidase N inhibitors to overcome cancer invasion and metastasis

Cao, Jiyue; Zhao, Cui; Dong, Hang; Xu, Qifu; Zhang, Yingjie

doi:10.1039/d1ra03629g

Cited by 3 publications

(6 citation statements)

References 26 publications

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“…The results are listed in Table 1 . Similar to SARs previously reported, the substituents on the terminal phenyl group of the diphenyl pyrazoline moiety could significantly impact the inhibitory activities against APN [ 30 ]. Comparing mono-substituted compounds 14a – 14f with a methyl group as R 1 , it was easily found that compounds ( 14a , 14d ) with ortho -substituents showed better inhibitory potencies against APN than their counterparts with meta -substituents ( 14b , 14e ) or para -substituents ( 14c , 14f ), respectively.…”

Section: Resultssupporting

confidence: 69%

“…Compounds 18a – 18h , 18j , 18k , 18m and 18n were reported before [ 30 ]. Compounds 18i , 18l , 18o , 18p and 18r – 18w were prepared following the procedure described for the compound 18q .…”

Section: Methodsmentioning

confidence: 97%

“…In our previous work, pyrazoline-based hydroxamate derivatives 13a and 13b showed the capacity of inhibiting APN ( Figure 2 ) [ 29 ]. Subsequently, optimization focused on the terminal phenyl group of the diphenyl pyrazoline core gave compound 13c with improved APN inhibitory activity relative to compounds 13a and 13b [ 30 ]. In this work, in order to extend the SARs of these series of compounds and find more potent APNIs, further optimization was focused on two phenyl groups of compounds 13a and 13b , leading to compound 14 .…”

Section: Introductionmentioning

confidence: 99%

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Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis

et al. 2022

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Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R1 = CH3, showed the best capacity for inhibiting APN with an IC50 value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His297, Glu298 and His301. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S2′ and S1 pockets via hydrophobic effects, respectively.

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Section: Resultssupporting

confidence: 69%

Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis

et al. 2022

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“…Such heterocyclic scaffolds having the nitrogen and/or sulfur atoms are involved in coordination of the zinc ion, and their rigidness is usually favored for formation of the desired hydrophobic interactions. 8,9…”

Section: Introductionmentioning

confidence: 99%

Naturally based pyrazoline derivatives as aminopeptidase N, VEGFR2 and MMP9 inhibitors: design, synthesis and molecular modeling

Batran,

Ahmed,

Awad

et al. 2024

RSC Adv.

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“…Proliferating active tumor cells may be inhibited by low expression of aminopeptidase. This provides the rationale that aminopeptidase can be used as a new therapeutic approach [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Transcriptomic Profiles Identified the Prediction of Prognosis and Drug Sensitivity of Aminopeptidase-Like 1 (NPEPL1) for Clear Cell Renal Cell Carcinoma

Wei¹,

Zhou

et al. 2023

Journal of Oncology

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Aminopeptidase-like 1 (NPEPL1) is a member of the aminopeptidase group that plays a role in the development and progression of various diseases. Expression of NPEPL1 has been reported to be involved in prostate, breast, and colorectal cancers. However, the role and mechanism of NPEPL1 in clear cell renal cell carcinoma (ccRCC) are unclear. The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases were used to predict the relationship between clinicopathological features and NPEPL1 expression. Changes in immune status and drug sensitivity with NPEPL1 expression were analyzed by the “CIBERSORT” function in R software. The results found that NPEPL1 expression was upregulated in ccRCC tissues, with expression progressively increasing with ccRCC stage and grade. Patients with high NPEPL1 expression presented with a poor prognosis across different clinicopathological features. Univariate and multivariate Cox regression analyses indicated that aberrant NPEPL1 expression was an independent risk factor for ccRCC. The nomogram showed that NPEPL1 expression improved the accuracy of predicting the prognosis of ccRCC patients. The Gene Ontology (GO) term enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that NPEPL1 may be involved in the development of ccRCC through the voltage-gated calcium channel complex, channel activity, cAMP signaling pathway, and oxytocin signaling pathway. The coexpression analysis found that NPEPL1 altered tumor characteristics by interacting with related genes. The “CIBERSORT” analysis showed that elevated NPEPL1 expression was followed by an enrichment of regulatory T cells and follicular helper T cells in the microenvironment. The drug sensitivity analysis found patients with high NPEPL1 expression had a higher benefit from axitinib, cisplatin, and GSK429286A. In conclusion, upregulation of NPEPL1 expression was involved in ccRCC prognosis and treatment. NPEPL1 could be used as a therapeutic target to guide clinical dosing.

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Development of pyrazoline-based derivatives as aminopeptidase N inhibitors to overcome cancer invasion and metastasis

Abstract: Compound 2k exhibited promising in vitro anti-invasion and in vivo anti-metastasis potencies, suggesting its prospect as an anti-invasion and anti-metastasis lead.

Cited by 3 publications

References 26 publications

Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis

Development of Hydroxamate Derivatives Containing a Pyrazoline Moiety as APN Inhibitors to Overcome Angiogenesis

Naturally based pyrazoline derivatives as aminopeptidase N, VEGFR2 and MMP9 inhibitors: design, synthesis and molecular modeling

Comprehensive Analysis of Transcriptomic Profiles Identified the Prediction of Prognosis and Drug Sensitivity of Aminopeptidase-Like 1 (NPEPL1) for Clear Cell Renal Cell Carcinoma

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