Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Almost all of the series and compounds exhibited higher acti

    2021-10-26

    Almost all of the series and compounds exhibited higher activities compared with the compounds in the other series. In these series, the tetrazole group was directly linked to a nitrogen atom of the amide group at the C-28 position, and the C-3 hydroxy group was either unmodified, oxidized, esterified, or changed to hydrazine. The unique feature of this series of Isoprenaline HCl compounds was that the tetrazole moiety was directly introduced to the C-28 position by means of an amide bond without any additional linkages. Compound showed the most potent inhibition of HIF-1α transcriptional activity with an IC value of 0.8 ± 0.2 µM. However, it did exert a moderate cytotoxic effect (IC 18.5 ± 0.2 µM). In contrast, we recorded a reasonable inhibitory activity without an enhancement of cytotoxicity when the C-3 hydroxy group was oxidized to a ketone, as shown for compound (IC 18.1 ± 0.2 µM). However, further modification of the C-3 hydroxy group to a phenylhydrazine derivative () resulted in increases in both the HIF-1α transcriptional inhibitory activity (IC 2.2 ± 0.1 µM) and cytotoxicity (IC 11.9 ± 0.2 µM). The results obtained for compounds – (IC 4.7 ± 0.2 µM 1.6 ± 0.2 µM, 1.4 ± 0.2 µM, 0.8 ± 0.2 µM, and 13.3 ± 0.2 µM respectively strongly suggested that the esterification of the C-3 hydroxy group could not only increase the HIF-1α inhibitory activity but also enhanced the cytotoxicity except for , indicating that the presence of a larger group in this position is detrimental for the development of a suitable HIF-1α inhibitor. Compound with the most desirable inhibitory activity against HIF-1α out of all the derivatives tested, was selected for further biological evaluation. As shown in , compound dose-dependently inhibited the luciferase activity in Hep3B cells (A) and concentration up to 30 µM did not adversely affect cell viability (B). In summary, several series of ursolic Isoprenaline HCl tetrazole derivatives were designed, synthesized, and evaluated for their HIF-1α inhibitory activities. Of the compounds tested, compound showed the most promising HIF-1α inhibitory activity with an IC of 4.7 ± 0.2 µM and did not show any significant cytotoxicity at a concentration of 30 µM against a Hep3B cell line. Furthermore, its inhibitory activity was comparable to compound B and eight times more potent than compound A. Analysis of the structure–activity relationships of the compounds inhibiting HIF-1α suggested that introduction of the tetrazole moiety at the C-28 position of UA is critical for increasing the HIF-1α inhibitory activity and a larger group at the C-3 position is detrimental for the development of a suitable HIF-1α inhibitor. Acknowledgements The work was supported by the National Science Foundation of China (No. 81660608) and the Natural Science Foundation of Jilin Province (No. 20160101218JC). We thank Anne M. O’Rourke, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.
    Introduction Primary liver cancer is one of the world's deadliest common malignancy and the third main cause of cancer-associated death. Hepatocellular carcinoma (HCC) accounts for 85%–90% of primary liver cancers and is refractory to nearly all currently available anti-cancer therapies [1]. Sorafenib, the multi-kinase inhibitor, is the first-line systemic therapy approved in hepatocellular carcinoma [2]. As the inhibitor of the Ras/Raf/MAPK and VEGFR/PDGFR signaling pathway, sorafenib is able to suppress tumor growth and angiogenesis, thereby delaying HCC progression with the prolongation of the patients' survival for almost 3 months [3]. However, the clinical application of sorafenib is largely limited by chemoresistance [4]. Therefore, it is critical to identify a novel molecular mechanism underlying sorafenib resistance in HCC, which might be helpful for improving the therapeutic efficacy of HCC patients.