Gelastatins and their hydroxamates as dual functional inhibitors for TNF-alpha converting enzyme and matrix metalloproteinases: synthesis, biological evaluation, and mechanism studies.
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 IC50's of 6, 23, and 28 nM, respectively. In addition, 2 were able to inhibit TNF-alpha 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-alpha inhibition was examined by RT-PCR and Western blot analyses. The relation of TACE and alpha-secretase was examined using cellular alpha-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.
Park
Song-Kyu
SK
Korea Research Institute of Bioscience and Biotechnology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-333, Republic of Korea.
Han
Sang Bae
SB
Lee
Kiho
K
Lee
Ho Jae
HJ
Kho
Yung Hee
YH
Chun
Hyokon
H
Choi
Yongseok
Y
Yang
Jae Young
JY
Yoon
Yeo Dae
YD
Lee
Chang-Woo
CW
Kim
Hwan Mook
HM
Choi
Hyun-Moo
HM
Tae
Hyun Seop
HS
Lee
Hee-Yoon
HY
Nam
Ky-Youb
KY
Han
Gyoonhee
G
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D020134:Catalytic Domain; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry*; D007118:Immunoassay; D020128:Inhibitory Concentration 50; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011422:Propionates / Q000737:chemistry* / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011422:Propionates; D011753:Pyrones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C106757:gelastatin A; C106758:gelastatin B; D052247:Nitric Oxide Synthase Type II; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse