PMID- 28375637
OWN - NLM
STAT- MEDLINE
DCOM- 20180604
LR  - 20240210
IS  - 1520-5126 (Electronic)
IS  - 0002-7863 (Print)
IS  - 0002-7863 (Linking)
VI  - 139
IP  - 15
DP  - 2017 Apr 19
TI  - Development of a General Aza-Cope Reaction Trigger Applied to Fluorescence 
      Imaging of Formaldehyde in Living Cells.
PG  - 5338-5350
LID - 10.1021/jacs.6b12460 [doi]
AB  - Formaldehyde (FA) is a reactive signaling molecule that is continuously produced 
      through a number of central biological pathways spanning epigenetics to 
      one-carbon metabolism. On the other hand, aberrant, elevated levels of FA are 
      implicated in disease states ranging from asthma to neurodegenerative disorders. 
      In this context, fluorescence-based probes for FA imaging are emerging as 
      potentially powerful chemical tools to help disentangle the complexities of FA 
      homeostasis and its physiological and pathological contributions. Currently 
      available FA indicators require direct modification of the fluorophore backbone 
      through complex synthetic considerations to enable FA detection, often limiting 
      the generalization of designs to other fluorophore classes. To address this 
      challenge, we now present the rational, iterative development of a general 
      reaction-based trigger utilizing 2-aza-Cope reactivity for selective and 
      sensitive detection of FA in living systems. Specifically, we developed a 
      homoallylamine functionality that can undergo a subsequent self-immolative 
      beta-elimination, creating a FA-responsive trigger that is capable of masking a 
      phenol on a fluorophore or any other potential chemical scaffold for related 
      imaging and/or therapeutic applications. We demonstrate the utility of this 
      trigger by creating a series of fluorescent probes for FA with excitation and 
      emission wavelengths that span the UV to visible spectral regions through caging 
      of a variety of dye units. In particular, Formaldehyde Probe 573 (FAP573), based 
      on a resorufin scaffold, is the most red-shifted and FA sensitive in this series 
      in terms of signal-to-noise responses and enables identification of alcohol 
      dehydrogenase 5 (ADH5) as an enzyme that regulates FA metabolism in living cells. 
      The results provide a starting point for the broader use of 2-aza-Cope reactivity 
      for probing and manipulating FA biology.
FAU - Bruemmer, Kevin J
AU  - Bruemmer KJ
FAU - Walvoord, Ryan R
AU  - Walvoord RR
FAU - Brewer, Thomas F
AU  - Brewer TF
FAU - Burgos-Barragan, Guillermo
AU  - Burgos-Barragan G
AD  - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, 
      United Kingdom.
FAU - Wit, Niek
AU  - Wit N
AD  - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, 
      United Kingdom.
FAU - Pontel, Lucas B
AU  - Pontel LB
AD  - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, 
      United Kingdom.
FAU - Patel, Ketan J
AU  - Patel KJ
AD  - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, 
      United Kingdom.
AD  - Department of Medicine, Addenbrooke's Hospital, University of Cambridge , 
      Cambridge CB2 2QQ, United Kingdom.
FAU - Chang, Christopher J
AU  - Chang CJ
AUID- ORCID: 0000-0001-5732-9497
LA  - eng
GR  - 13647/CRUK_/Cancer Research UK/United Kingdom
GR  - MC_U105178811/MRC_/Medical Research Council/United Kingdom
GR  - R01 ES028096/ES/NIEHS NIH HHS/United States
GR  - T32 GM066698/GM/NIGMS 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 - 20170404
PL  - United States
TA  - J Am Chem Soc
JT  - Journal of the American Chemical Society
JID - 7503056
RN  - 0 (Aza Compounds)
RN  - 1HG84L3525 (Formaldehyde)
SB  - IM
MH  - Aza Compounds/*chemistry
MH  - Cell Survival
MH  - Formaldehyde/*analysis/*chemistry
MH  - HEK293 Cells
MH  - Humans
MH  - Molecular Structure
MH  - *Optical Imaging
PMC - PMC5501373
COIS- The authors declare no competing financial interest.
EDAT- 2017/04/05 06:00
MHDA- 2018/06/05 06:00
PMCR- 2017/07/07
CRDT- 2017/04/05 06:00
PHST- 2017/04/05 06:00 [pubmed]
PHST- 2018/06/05 06:00 [medline]
PHST- 2017/04/05 06:00 [entrez]
PHST- 2017/07/07 00:00 [pmc-release]
AID - 10.1021/jacs.6b12460 [doi]
PST - ppublish
SO  - J Am Chem Soc. 2017 Apr 19;139(15):5338-5350. doi: 10.1021/jacs.6b12460. Epub 
      2017 Apr 4.