Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies

Song Kyu Park; Sang Bae Han; Kiho Lee; Ho Jae Lee; Yung Hee Kho; Hyokon Chun; Yongseok Choi; Jae Young Yang; Yeo Dae Yoon; Chang Woo Lee; Hwan Mook Kim; Hyun Moo Choi; Hyun Seop Tae; Hee Yoon Lee; Ky Youb Nam; Gyoonhee Han

doi:10.1016/j.bbrc.2005.12.219

Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies

Song Kyu Park
, Sang Bae Han
, Kiho Lee
, Ho Jae Lee
, Yung Hee Kho
, Hyokon Chun
, Yongseok Choi
, Jae Young Yang
, Yeo Dae Yoon
, Chang Woo Lee
, Hwan Mook Kim^*
, Hyun Moo Choi
, Hyun Seop Tae
, Hee Yoon Lee
, Ky Youb Nam
, Gyoonhee Han

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by 1 step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC ₅₀'s of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-α production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-α inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and α-secretase was examined using cellular α-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode for the further analogue design.

Original language	English
Pages (from-to)	627-634
Number of pages	8
Journal	Biochemical and biophysical research communications
Volume	341
Issue number	2
DOIs	https://doi.org/10.1016/j.bbrc.2005.12.219
Publication status	Published - 2006 Mar 10
Externally published	Yes

Bibliographical note

Funding Information:
This research was supported by a Grant (0405-NS01-0704-0001) of the Korean Health 21 R&D Project, Ministry of Health and Wellfare, and the Ministry of Commerce, Industry and Energy, the Republic of Korea.

Keywords

Inhibitors
TNFα converting enzyme
Tumor necrosis factor alpha
α-Secretase

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2005.12.219

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Park, S. K., Han, S. B., Lee, K., Lee, H. J., Kho, Y. H., Chun, H., Choi, Y., Yang, J. Y., Yoon, Y. D., Lee, C. W., Kim, H. M., Choi, H. M., Tae, H. S., Lee, H. Y., Nam, K. Y., & Han, G. (2006). Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies. Biochemical and biophysical research communications, 341(2), 627-634. https://doi.org/10.1016/j.bbrc.2005.12.219

Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies. / Park, Song Kyu; Han, Sang Bae; Lee, Kiho et al.
In: Biochemical and biophysical research communications, Vol. 341, No. 2, 10.03.2006, p. 627-634.

Research output: Contribution to journal › Article › peer-review

Park, SK, Han, SB, Lee, K, Lee, HJ, Kho, YH, Chun, H, Choi, Y, Yang, JY, Yoon, YD, Lee, CW, Kim, HM, Choi, HM, Tae, HS, Lee, HY, Nam, KY & Han, G 2006, 'Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies', Biochemical and biophysical research communications, vol. 341, no. 2, pp. 627-634. https://doi.org/10.1016/j.bbrc.2005.12.219

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abstract = "The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by 1 step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC 50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-α production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-α inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and α-secretase was examined using cellular α-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode for the further analogue design.",

keywords = "Inhibitors, TNFα converting enzyme, Tumor necrosis factor alpha, α-Secretase",

author = "Park, \{Song Kyu\} and Han, \{Sang Bae\} and Kiho Lee and Lee, \{Ho Jae\} and Kho, \{Yung Hee\} and Hyokon Chun and Yongseok Choi and Yang, \{Jae Young\} and Yoon, \{Yeo Dae\} and Lee, \{Chang Woo\} and Kim, \{Hwan Mook\} and Choi, \{Hyun Moo\} and Tae, \{Hyun Seop\} and Lee, \{Hee Yoon\} and Nam, \{Ky Youb\} and Gyoonhee Han",

note = "Funding Information: This research was supported by a Grant (0405-NS01-0704-0001) of the Korean Health 21 R\&D Project, Ministry of Health and Wellfare, and the Ministry of Commerce, Industry and Energy, the Republic of Korea. ",

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AU - Park, Song Kyu

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AU - Lee, Kiho

AU - Lee, Ho Jae

AU - Kho, Yung Hee

AU - Chun, Hyokon

AU - Choi, Yongseok

AU - Yang, Jae Young

AU - Yoon, Yeo Dae

AU - Lee, Chang Woo

AU - Kim, Hwan Mook

AU - Choi, Hyun Moo

AU - Tae, Hyun Seop

AU - Lee, Hee Yoon

AU - Nam, Ky Youb

AU - Han, Gyoonhee

N1 - Funding Information: This research was supported by a Grant (0405-NS01-0704-0001) of the Korean Health 21 R&D Project, Ministry of Health and Wellfare, and the Ministry of Commerce, Industry and Energy, the Republic of Korea.

PY - 2006/3/10

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AB - The hydroxamic acid analogues (2) of the natural product gelastatins (1) were prepared by 1 step conversion reaction. The synthetic analogues (2) showed potent enzymatic inhibitory activities against MMP-2, MMP-9, and TACE IC 50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-α production effectively in mice as well as in a macrophage cell line, RAW 264.7. The protective effect of 2 also was examined on LPS-induced acute septic shock model. The mechanism of TNF-α inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and α-secretase was examined using cellular α-secretase assays on IMR-32 and SH-SY5Y cell lines. The docking mode of 2 with the catalytic domain of TACE was illustrated to analyze the binding mode for the further analogue design.

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Gelastatins and their hydroxamates as dual functional inhibitors for TNF-α converting enzyme and matrix metalloproteinases: Synthesis, biological evaluation, and mechanism studies

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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