Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma

Zhai, Shiyang; Zhang, Huimin; Chen, Rui; Wu, Jiangxia; Ai, Daiqiao; Tao, Shunming; Cai, Yike; Zhang, Jiquan; Wang, Ling

doi:10.1016/j.ejmech.2021.113824

Cited by 13 publications

(22 citation statements)

References 48 publications

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“…Compound 102 further induced apoptosis and cell cycle arrest at Pre-G1 and G2/M phases. Zhai and co-workers [ 97 ] demonstrated that compound 103 exhibited excellent antiproliferative activity against HepG2 cells with an IC 50 of 1.61 µM compared to the reference compounds (MLN0128, IC 50 = 2.13 µM and SAHA, IC 50 = 2.26 µM). Compound 103 showed significant selective cytotoxicity against HepG2 cells over normal human liver cells (L-O2) with a high SI value of 15.41.…”

Section: Six-membered Heterocyclic Compoundsmentioning

confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

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Heterocyclic compounds are a class of compounds of natural origin with favorable properties and hence have major pharmaceutical significance. They have an exceptional adroitness favoring their use as diverse smart biomimetics, in addition to possessing an active pharmacophore in a complex structure. This has made them an indispensable motif in the drug discovery field. Heterocyclic compounds are usually classified according to the ring size, type, and the number of heteroatoms present in the ring. Among different heterocyclic ring systems, nitrogen heterocyclic compounds are more abundant in nature. They also have considerable pharmacological significance. This review highlights recent pioneering studies in the biological assessment of nitrogen-containing compounds, namely: triazoles, tetrazoles, imidazole/benzimidazoles, pyrimidines, and quinolines. It explores publications between April 2020 and February 2022 and will benefit researchers in medicinal chemistry and pharmacology. The present work is organized based on the size of the heterocyclic ring.

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Section: Six-membered Heterocyclic Compoundsmentioning

confidence: 99%

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Ebenezer

Jordaan

Carena

et al. 2022

IJMS

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“…■ EXPERIMENTAL SECTION Chemistry. All start reagents were purchased from Leyan.com and Bide Pharmatech Ltd. 1 H NMR and 13 C NMR spectra were recorded using a Bruker DRX spectrometer with 400 MHz and tetramethylsilane (TMS) as an internal standard. HRMS data were recorded using a SCI EX X500e Q TOF LC/MS system at the Shandong Institute for Food and Drug Control.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 ): δ 9.79 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 5.57 (s, 2H), 3.63− 3.60 (m, 2H), 3.48−3.43 (m, 2H), 2.45 (t, J = 6.6 Hz, 2H), 1.94 (t, J = 7.3 Hz, 2H), 1.57−1.54 (m, 4H), 1.43−1.34 (m, 4H), 1.06 (s, 3H). 13 3 -hydroxyisophthalamide (8h). 8h was synthesized in the same way as 8a, yield: 45%, mp 210−212 °C.…”

Section: -((1-(6-amino-5-(23-dichlorophenyl)pyrazin-2-yl)-4-methylpip...mentioning

confidence: 99%

“…Among them, the zinc-dependent class I HDACs are overexpressed in many types of cancer and have become attractive targets for anticancer therapy. , To date, five HDAC inhibitors have been approved for the clinical treatment of hematological malignancies (Figure ). − …”

Section: Introductionmentioning

confidence: 99%

“…11,12 To date, five HDAC inhibitors have been approved for the clinical treatment of hematological malignancies (Figure 1). 13 The RAS-ERK pathway is a major signaling cascade in cancer. 16 As an oncogene, SHP2 is located upstream of the RAS-ERK pathway and can fully activate the RAS-ERK pathway to regulate the survival and proliferation of cancer cells.…”

Section: ■ Introductionmentioning

confidence: 99%

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Both Src homology-2 domain-containing phosphatase 2 (SHP2) and histone deacetylase (HDAC) are important oncoproteins and potential immunomodulators. In this study, we first observed a synergistic antiproliferation effect of an allosteric SHP2 inhibitor (SHP099) and HDAC inhibitor (SAHA) in MV4-11 cells. Inspired by this result, a series of SHP2/HDAC dual inhibitors were designed based on the pharmacophore fusion strategy. Among these inhibitors, the most potent compound 8t showed excellent inhibitory activities against SHP2 (IC50 = 20.4 nM) and HDAC1 (IC50 = 25.3 nM). In particular, compound 8t exhibited improved antitumor activities compared with those of SHP099 and SAHA in vitro and in vivo. Our study also indicated that treatment with 8t could trigger efficient antitumor immunity by activating T cells, enhancing the antigen presentation function and promoting cytokine secretion. To our knowledge, we report the first small molecular SHP2/HDAC dual inhibitor and demonstrate a new strategy for cancer immunotherapy.

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Histone deacetylases (HDACs) are a class of epigenetic enzymes that are closely related to tumorigenesis and suppress the expression of tumor suppressor genes. Whereas the HDACs inhibitors can release DNA into the cytoplasm and trigger innate immunity. However, the high density of chromatin limits DNA damage and release. In this study, suitable nanosized CycNHOH NPs (150 nm) and CypNHOH NPs (85 nm) efficiently accumulate at the tumor site due to the enhanced permeability and retention (EPR) effect. In addition, robust single‐linear oxygen generation and good photothermal conversion efficiency under NIR laser irradiation accelerated the DNA damage process. By effectively initiating immune cell death, CypNHOH NPs activated both innate and adaptive immunity by maturing dendritic cells, infiltrating tumors with natural killer cells, and activating cytotoxic T lymphocytes, which offer a fresh perspective for the development of photo‐immunotherapy.

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Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma

Cited by 13 publications

References 48 publications

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

An Overview of the Biological Evaluation of Selected Nitrogen-Containing Heterocycle Medicinal Chemistry Compounds

Discovery of Novel Src Homology-2 Domain-Containing Phosphatase 2 and Histone Deacetylase Dual Inhibitors with Potent Antitumor Efficacy and Enhanced Antitumor Immunity

Near‐Infrared Light‐Driven Nanoparticles for Cancer Photoimmunotherapy by Synergizing Immune Cell Death and Epigenetic Regulation

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