Synthesis and biological evaluation of 2-epi-jaspine B analogs as selective sphingosine kinase 1 inhibitors

Yang, Haoran; Liu, Ying; Chai, Huining; Yakura, Takayuki; Liu, Bo; Yao, Qingqiang

doi:10.1016/j.bioorg.2019.103369

Cited by 13 publications

(8 citation statements)

References 29 publications

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“…The SphKs assays were carried out as described previously. 19 From Table 1, it can be seen that the compounds numbered S2532 and S2118 have good SphK1 inhibitory effects. So, we continued to evaluate their IC 50 value against SphK1 and SphK2.…”

Section: Resultsmentioning

confidence: 99%

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L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation

Yang

Zhi

Yao

et al. 2021

Journal of Chemical Research

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Sphingosine kinases (SphKs) are a class of lipid kinases, that have received extensive attention as important rate-limiting enzyme in tumor. Inhibition of the activity of SphK1 can lead to an anticancer effect. Herein, we describe the discovery process and biological characteristics of a new SphK1 inhibitor, ascorbyl palmitate, discovered through computer-aided drug design. Biochemical experiments show that ascorbyl palmitate has a strong inhibitory effect on SphK1, with an IC50 value of 6.4 μM. The MTT experiment showed that ascorbyl palmitate had anti-cancer effects toward the U87, A549, 22RV1, and A375 cell lines. Among them, ascorbyl palmitate has prominent inhibitory activity against the 22RV1 cell line, with an IC50 value of 41.57 μM. To explore the structure–activity relationship, four ascorbyl palmitate derivatives were synthesized and tested for kinase activity. The outstanding effect of ascorbyl palmitate toward SphK1 and its known non-toxicity suggest that ascorbyl palmitate may be a lead compound for the development of effective SphK1 anti-cancer inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…The SphKs assays were carried out as described previously. 19 The assay was performed using Kinase-Glo Plus luminescence kinase assay kit (purchased from Promega, Fitchburg, USA). It measures kinase activity by quantitating the amount of ATP remaining in solution following a kinase reaction.…”

Section: Methodsmentioning

confidence: 99%

L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation

Yang

Zhi

Yao

et al. 2021

Journal of Chemical Research

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“…Although this view has been controversial, there is no doubt that inhibition of SphK1 activity plays an important role in the treatment of cancer, inflammation and other diseases [ 11 ]. In previous studies, we found that SphK1 inhibitors have anti-inflammatory and anticancer activities, which makes the discovery of novel drugs more promising [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors

Geng

Chen

et al. 2022

Molecules

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Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 μM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 μM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma.

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“…Moreover, analog YHR17 developed from 2- epi -jaspine B possesses 125-fold selectivity over SphK2 and inhibits A375 cell line proliferation at very low concentrations (IC 50 = 0.68 to 5.68 μM). 50 Icaritin, a flavonoid, inhibits SphK1 activity and is cytotoxic to hepatocellular carcinoma both in vitro and in vivo. ( 51 ) Hispidulin, another flavonoid, is known to inhibit SphK1 activity and induces apoptosis in Caki-2 and A498 cell lines.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer

et al. 2020

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The sphingosine kinase-1/sphingosine-1-phosphate pathway is linked with the cancer progression and survival of the chemotherapy-challenged cells. Sphingosine kinase-1 (SphK1) has emerged as an attractive drug target, but their inhibitors from natural sources are limited. In this study, we have chosen harmaline, one of the β-carboline alkaloids, and report its mechanism of binding to SphK1 and subsequent inhibition. Molecular docking combined with fluorescence binding studies revealed that harmaline binds to the substrate-binding pocket of SphK1 with an appreciable binding affinity and significantly inhibits the kinase activity of SphK1 with an IC 50 value in the micromolar range. The cytotoxic effect of harmaline on non-small-cell lung cancer cells by MTT assay was found to be higher for H1299 compared to A549. Harmaline induces apoptosis in non-small-cell lung carcinoma cells (H1299 and A549), possibly via the intrinsic pathway. Our findings suggest that harmaline could be implicated as a scaffold for designing potent anticancer molecules with SphK1 inhibitory potential.

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Synthesis and biological evaluation of 2-epi-jaspine B analogs as selective sphingosine kinase 1 inhibitors

Cited by 13 publications

References 29 publications

L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation

L-ascorbyl 6-palmitate as lead compound targeting SphK1: an in silico and in vitro investigation

Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors

Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer

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