PMID- 20637638
OWN - NLM
STAT- MEDLINE
DCOM- 20101206
LR  - 20220410
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 18
IP  - 16
DP  - 2010 Aug 15
TI  - The marine sponge metabolite mycothiazole: a novel prototype mitochondrial 
      complex I inhibitor.
PG  - 5988-94
LID - 10.1016/j.bmc.2010.06.072 [doi]
AB  - A natural product chemistry-based approach was applied to discover small-molecule 
      inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis 
      marine sponge extract yielded mycothiazole (1), a solid tumor selective compound 
      with no known mechanism for its cell line-dependent cytotoxic activity. Compound 
      1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated 
      with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 
      1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 
      1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone 
      oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, 
      and other complex I inhibitors, mycothiazole is a mixed 
      polyketide/peptide-derived compound with a central thiazole moiety. The exquisite 
      potency and structural novelty of 1 suggest that it may serve as a valuable 
      molecular probe for mitochondrial biology and HIF-mediated hypoxic signaling.
CI  - Copyright 2010 Elsevier Ltd. All rights reserved.
FAU - Morgan, J Brian
AU  - Morgan JB
AD  - Department of Pharmacognosy, School of Pharmacy, University of Mississippi, 
      University, MS 38677, USA.
FAU - Mahdi, Fakhri
AU  - Mahdi F
FAU - Liu, Yang
AU  - Liu Y
FAU - Coothankandaswamy, Veena
AU  - Coothankandaswamy V
FAU - Jekabsons, Mika B
AU  - Jekabsons MB
FAU - Johnson, Tyler A
AU  - Johnson TA
FAU - Sashidhara, Koneni V
AU  - Sashidhara KV
FAU - Crews, Phillip
AU  - Crews P
FAU - Nagle, Dale G
AU  - Nagle DG
FAU - Zhou, Yu-Dong
AU  - Zhou YD
LA  - eng
GR  - CA047135/CA/NCI NIH HHS/United States
GR  - R01 CA047135/CA/NCI NIH HHS/United States
GR  - R01 CA098787-05A2/CA/NCI NIH HHS/United States
GR  - R01 CA098787-06/CA/NCI NIH HHS/United States
GR  - C06 RR014503/RR/NCRR NIH HHS/United States
GR  - CA98787/CA/NCI NIH HHS/United States
GR  - P20RR021929/RR/NCRR NIH HHS/United States
GR  - P20 RR021929/RR/NCRR NIH HHS/United States
GR  - C06 RR-14503-01/RR/NCRR NIH HHS/United States
GR  - R01 CA098787/CA/NCI NIH HHS/United States
GR  - R56 CA098787-05A1/CA/NCI NIH HHS/United States
GR  - R56 CA098787/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100625
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Thiazoles)
RN  - 0 (mycothiazole)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Electron Transport Complex I/*antagonists & inhibitors/metabolism
MH  - Enzyme Inhibitors/isolation & purification/*pharmacology
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*antagonists & inhibitors/genetics/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
MH  - Neovascularization, Pathologic/drug therapy
MH  - Neurons/drug effects
MH  - Porifera/*chemistry
MH  - Rats
MH  - Thiazoles/isolation & purification/*pharmacology
PMC - PMC2918693
MID - NIHMS218547
EDAT- 2010/07/20 06:00
MHDA- 2010/12/14 06:00
PMCR- 2011/08/15
CRDT- 2010/07/20 06:00
PHST- 2010/05/19 00:00 [received]
PHST- 2010/06/18 00:00 [revised]
PHST- 2010/06/21 00:00 [accepted]
PHST- 2010/07/20 06:00 [entrez]
PHST- 2010/07/20 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2011/08/15 00:00 [pmc-release]
AID - S0968-0896(10)00600-0 [pii]
AID - 10.1016/j.bmc.2010.06.072 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2010 Aug 15;18(16):5988-94. doi: 10.1016/j.bmc.2010.06.072. Epub 
      2010 Jun 25.