N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure–activity relationships and X-ray crystallographic studies

Li, Minglei; Liu, Shengjie; Chen, Hui; Zhou, Xinyu; Zhou, Jing; Zhou, Shuang-Yong; Yuan, Haoliang; Xu, Qing‐Long; Li, Jun; Cheng, Keguang; Sun, Hongbin; Wang, Yue; Chen, Caiping; Wen, Xiaoan

doi:10.1016/j.ejmech.2020.112279

Cited by 25 publications

(20 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 10-membered core exhibits minor distortions from planarity having a r.m.s. deviation of 0.0319 Å with the maximum deviation of 0.0605(13) Å noted for the C3a atom; the dihedral angle between the veand six-membered rings ¼ 4.52 (8) . The dihedral angles between the central plane and the planes through the N-bound bromo-and methoxy-phenyl rings are 13.15 (6) and 58.81(3) , respectively, are indicative of signicant twisting in the molecule; the dihedral angle between the outer rings is 52.82 (4) .…”

Section: X-ray Crystallographymentioning

confidence: 88%

“…1 H NMR (300 MHz, DMSO-d 6 ): d 5.16 (3H, s, CH 2 Ph),6.85 (1H, t, 3 J ¼ 7 3. Hz, H-4 0 ), 7.24 (2H, t, 3 J ¼ 7 8. Hz, H-3 0 and H-5 0 ), 7.27-7.37 (5H, m, CH 2 Ph), 7.66 (2H, d, 3 J ¼ 7.7 Hz, H-2 0 and H-6 0 ), 7.91 (1H, s, NH), 8.51 (1H, s, H-6), 12.93 (1H, s, NH).13 C NMR (75 MHz, DMSO-d 6 ): d 47.9 (CH 2 ), 93.3 (C-3a), 116.4 1 H NMR (300 MHz, DMSO-d 6 ): d 5.16 (2H, s, CH 2 ), 7.24-7.37 (7H, m, H-3 0 , H-5 0 , H-2 00 , H-3 00 , H-4 00 , H-5 00 and H-6 00 ), 7.72 (2H, d, 3 J ¼ 8.9 Hz, H-2 0 and H-6 0 ), 8.21 (1H, s, NH), 8.52 (1H, s, H-6), 8.22 (1H, s, NH), 8.52 (1H, s, H-6), 13.01 (1H, s, NH).…”

mentioning

confidence: 99%

“…Found: C, 54.48; H, 3.65; N, 17.54. 1 1 H NMR (300 MHz, DMSO-d 6 ): d 5.15 (2H, s, CH 2 ), 7.19 (2H, dd, 3 J HF ¼ 8.8 Hz, 3 J HH ¼ 8 8. Hz, H-3 00 and H-5 00 ), 7.1 H NMR (300 MHz, DMSO-d 6 ): d 3.83 (3H, s, OCH 3 ), 3.87 (3H, s, OCH 3 ), 6.87 (1H, ddd, 4 J ¼ 1.6 Hz, 3 J ¼ 7.6 Hz, 3 J ¼ 7 6.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones

Tiekink

Dolzhenko

2022

RSC Adv.

View full text Add to dashboard Cite

show abstract

Section: X-ray Crystallographymentioning

confidence: 88%

mentioning

confidence: 99%

See 1 more Smart Citation

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones

Tiekink

Dolzhenko

2022

RSC Adv.

View full text Add to dashboard Cite

show abstract

“…These technologies will be of great help in our future discovery of antitumor and immune regulatory signal pathways of DUBs. New technologies such as X-ray crystallographic analysis, virtual screening and molecular dynamics simulations have also been used to develop specific DUBs inhibitors ( Li M. et al, 2020 ). Targeted DUBs is expected to become a new strategy to regulate TAIMs, strengthen immunotherapy, and eliminate CSCs completely to reduce tumor recurrence.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

Guo

Xia

Deng

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.

show abstract

“…The heterocyclic pyrazolo[3,4- d ]pyrimidine system has interesting chemical properties and a wide spectrum of biological activities [ 22 ]. New derivatives of pyrazolo[4,3- e ][1,2,4] triazolo[1,5- c ]pyrimidine act as kinase inhibitors and anticancer agents [ 22 , 23 , 24 , 25 , 26 ]. In a continuation of these efforts, we report the design, synthesis, and bioassay for pyrazolo-[4,3- e ][1,2,4]triazolopyrimidine [ 1 , 2 , 3 ] and the crystal structure of 7-(4-bromophenyl)-9-(pyridin-4-yl)-7 H -pyrazolo[4,3- e ][1,2,4]triazolo[1,5- c ]pyrimidine [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

et al. 2021

View full text Add to dashboard Cite

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

show abstract

N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure–activity relationships and X-ray crystallographic studies

Cited by 25 publications

References 29 publications

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Contact Info

Product

Resources

About