Photoreaction
Covalent bond formation upon irradiation:
Identical bioactivity:
The photoreactive modification should not affect bioactivity therefore ideally the photoreactive moiety is as small as possible. Azide groups are optimal modifications as they only add 3 nitrogen atoms to the molecule.
Absorbance properties:
For in vivo systems, light irradiation is a stress factor which needs to be minimized and preferably longer wavelength light should be applied as it has deeper penetration and it is less phototoxic.
In order to minimize irradiation, efficient photoactivation is required, therefore the absorbance properties of the compound may have to be optimized. Photoreactive compounds which absorb at longer wavelength and have higher extinction coefficient work better.
Examples
Azidoblebbistatin
Molecular tattoo: subcellular confinement of drug effects.Képiró et al. Chem Biol. 2015 Apr 23;22(4):548-558.
Azidoblebbistatin, a photoreactive myosin inhibitor.Képiró et al. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9402-7.
Azido-azakenpaullone
The photoreactive derivative of the glycogen synthase kinase-3 beta (GSK-3B) inhibitor
1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3 beta.Kunick et al. Bioorg Med Chem Lett. 2004 Jan 19;14(2):413-6.
ANQX
Photoreactive AMPA receptor antagonist
Photochemical inactivation analysis of temporal dynamics of postsynaptic native AMPA receptors in hippocampal slices.Kamiya H. J Neurosci. 2012 May 9;32(19):6517-24. doi: 10.1523/JNEUROSCI.0720-12.2012.
6-Azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX) forms an irreversible bond to the active site of the GluR2 AMPA receptor. Cruz et al. J Med Chem. 2008 Sep 25;51(18):5856-60. doi: 10.1021/jm701517b.
Photochemically knocking out glutamate receptors in vivo. Chambers et al J Am Chem Soc. 2004 Nov 3;126(43):13886-7.
Other uses of photoreactive compounds
Photoreactive compounds developed for molecular tattoo may be used for other applications as well.
In enzyme structural studies azidated inhibitors are powerful tools as permanent enzyme-inhibitor complexes are formed and the saturation of the binding site can be achieved.
In target search for drug discovery the covalent interaction can be used to fish systematically all weakly and strongly binding targets for a drug or a lead molecule. This way determination of small molecule interactome becomes highly effective, especially, the weak interactions can be determined, which was not possible before.