Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition

Li, Na; Ou, Jinfeng; Bao, Na; Cheng, Chen; Shi, Zhixian; Chen, Li

doi:10.1016/j.bioorg.2020.104208

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…The p-JAK2 can mediate the phosphorylation of STAT3 at Tyr705 site. [23] Based on what have been discussed above, mogrol and its derivative can inhibit the phosphorylation level of STAT3. To explore whether M2h and M6a effect on JAK2/STAT3 signal pathway, the p-JAK2 and p-STAT3 protein expression levels were analyzed (Table S3 and S4).…”

Section: Effects On Jak2/stat3 Signal Pathwaymentioning

confidence: 94%

Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway

Song

2021

Chemistry & Biodiversity

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In attempt to enhance the antiproliferative activity of mogrol, two series of ester derivatives modified at C 3 À OH and C 11 À OH were designed and synthesized. The activity against human cancer cells including A549, NCI-H460 and CNE1 was screened by Cell Counting Kit-8 (CCK8) assay. According to the results, modifications of the mogrol core through introduction of different ester scaffolds drastically improved the cytotoxicity, and some of the derivatives exhibited even higher activity than the positive drug. Among them, compound M2h exhibited nearly 4 times more cytotoxic than 5-Fu against CNE1 cells, derivative M6c showed ten times higher activity with the IC 50 value of 10.59 μM than mogrol against NCI-H460 cells, and compound M6a which contained one 1,2,3triazole motif showed the strongest activity with an three folds lower IC 50 value than mogrol. Furthermore, the most potent compound M2h could lead to cell cycle arrest at G2 phase on CNE1 cell lines and M6a induced G1 phase arrest on A549 cell lines. It was noteworthy that both M2h and M6a regulated signal transducer and activator of transcription 3 (STAT3) signal pathway through inhibiting phosphorylation of Janus Kinase 2 (JAK2) and STAT3, and simultaneously increasing the protein level of downstream cyclin p21.

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Section: Effects On Jak2/stat3 Signal Pathwaymentioning

confidence: 94%

Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway

Song

2021

Chemistry & Biodiversity

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“…It shares a very similar structure with efficient STAT3-SH2 inhibitors (1,4-naphthoquinone core, like STA-21 and LLL-3) and extends into the pTyr705 pocket via forming a hydrogen bond with Ser611 and cation-π interaction with Lys591, but it could not interact with the side pocket. In order to increase the STAT3 binding affinity of PL, the Sun group introduced an aromatic ring in PL to enable new derivatives to embed in site pTyr705 and side pocket simultaneously . SARs revealed that the hydroxyl group at C-5 was crucial for the STAT3 inhibitory activity.…”

Section: Recent Development Of Stat3 Inhibitorsmentioning

confidence: 99%

Section: Recent Development Of Stat3 Inhibitorsmentioning

confidence: 99%

“…In order to increase the STAT3 binding affinity of PL, the Sun group introduced an aromatic ring in PL to enable new derivatives to embed in site pTyr705 and side pocket simultaneously. 86 SARs revealed that the hydroxyl group at C-5 was crucial for the STAT3 inhibitory activity. Additionally, the introduction of additional groups to the aromatic ring and suitable linkers are also beneficial for the activity.…”

Section: Recent Development Of Stat3 Inhibitorsmentioning

confidence: 99%

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Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation

Dong

Cheng

Zhang³

et al. 2021

J. Med. Chem.

112

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Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various biological processes, including proliferation, metastasis, angiogenesis, immune response, and chemoresistance. In normal cells, STAT3 is tightly regulated to maintain a transiently active state, while persistent STAT3 activation occurs frequently in cancers, associating with a poor prognosis and tumor progression. Targeting the STAT3 protein is a potentially promising therapeutic strategy for tumors. Although none of the STAT3 inhibitors has been marketed yet, a few of them have succeeded in entering clinical trials. This Review aims to systematically summarize the progress of the last 5 years in the discovery of directive STAT3 small-molecule inhibitors and degraders, focusing primarily on their structural features, design strategies, and bioactivities. We hope this Review will shed light on future drug design and inhibitor optimization to accelerate the discovery process of STAT3 inhibitors or degraders.

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“…108,109 Plumbagin is isolated from root of Plumbago zeylanica L., possessing potent antitumor activity. 110 It also exerts anti-inflammatory effect after SCI. Plumbagin (20 mg/kg, intraspinal injection or i.p.…”

Section: Dovepressmentioning

confidence: 99%

Neuroinflammation and Modulation Role of Natural Products After Spinal Cord Injury

Yan

Zhang

2021

JIR

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Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition

Cited by 11 publications

References 24 publications

Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway

Synthesis and Antiproliferative Activity of Ester Derivatives of Mogrol through JAK2/STAT3 Pathway

Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation

Neuroinflammation and Modulation Role of Natural Products After Spinal Cord Injury

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