Protecting groups with increased photosensitivities

Details Protecting groups with increased photosensitivities Protecting groups with increased photosensitivities

1998-11-20

2002-10-29

Celsa, Bennett (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C536S001110, C536S017300, C436S071000, C530S300000, C546S152000, C546S153000

Reexamination Certificate

active

06472541

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to protecting groups that can be removed by irradiation.
Protecting groups can be used to mask compounds, or portions of compounds, from interacting in chemical or biological systems. For example, a protecting group can prevent a compound from undergoing a chemical reaction by changing the chemical nature of a functionality. In another example, a protecting group can mask or conceal a biological response induced by the compound in a biological system, both in vivo and in vitro (e.g., in a cell, a tissue, or an assay). One class of protecting group of particular interest for use in biological systems are photolabile protecting groups. Photolabile protecting groups, sometimes called caging groups, have become a mainstay of organic synthesis, biotechnology, and cell biology, because cleavage by light is a very mild deprotection step that is usually orthogonal to other experimental manipulations. The outstanding spatial and temporal precision with which light can be controlled enables diverse applications such as photolithographic construction of complex peptide and oligonucleotide arrays, or physiological release (“uncaging”) of bioactive substances in cells and tissues. Examples of caging groups that can be removed from a compound by exposing the compound to light, for example, by a flash of UV, are described in Adams, S. R. and Tsien, R. Y.
Annual Rev. Physiology
55:755-784 (1993), incorporated herein by reference.
In general, the protecting groups mask charged (e.g., carboxylate or phosphate) or polar (e.g., amine, sulfhydryl, or hydroxyl) functionalities of the compounds, which can increase their hydrophobicity and their membrane permeability. Before photolysis, these caged compounds are biologically or chemically inactive because at least one of the key functionalities is blocked. The activity of the molecule can be triggered by a pulse of light, which releases the protecting group. In this way, photolabile protecting groups can be removed from a protected compound by irradiation to control release of the compound both spatially and temporally. In particular, compounds of biologically active products can be used to probe biological effects of the compounds. While uncaging can take place in a sample, such as a solution, a tissue sample, or in live cells, this strategy is very valuable for in vivo biological application. It allows control of the onset of bioactivity in living cells with millisecond temporal precision.
Examples of photolabile protecting groups that have been used to cage biomolecules include 2-nitrobenzyl, 1-(2-nitrophenyl)ethyl, 4,5-dimethoxy-2-nitrobenzyl, and -carboxy-4,5-dimethoxy-2-nitrobenzyl. The mechanism of photo-deprotection of caging groups and the applications of caging compounds have been reviewed. See, for example, McCray, J. A. and Trentham, D. R.,
Annu. Rev. Biophys. Biophys. Chem.,
18:239-270 (1989), and Adams, S. R. and Tsien, R. Y.,
Annu. Rev. Physiol.
55:755-784 (1993). Examples of caged molecules which have had successful applications in biology include caged cAMP (see, e.g., Walker, J. W., et al.,
Methods Enzymol.
172:288-301 (1989), and Wootton, J. F. and Trentham, D. R.,
NATO ASI Ser. C
272 (1989)), caged nitric oxide (see, e.g., Lev-Ram, V., et al.,
Neuron
15:407-415 (1995), and Makings, L. R. and Tsien, R. Y.,
J. Biol. Chem.
269:6282-6285 (1994)), caged fluorescein (see, e.g., Krafft, G. A., et al.,
J. Am. Chem. Soc.
110:301 (1988)), caged calcium (see, e.g., Adams, S. R., et al.,
J. Am. Chem. Soc.
110:3212 (1988), and Tsien, R. Y. and Zucker, R. S.,
Biophys. J.
50:843-853 (1986)), caged glutamate (see, e.g., Callaway, E. M. and Katz, L. C.,
Proc. Natl. Acad. Sci. U.S.A.
90:7661-7665 (1993), Wilcox, M., et al.,
J. Org. Chem.
55:1585 (1990), and Corrie, J. E., et al.,
J. Physiol. (Lond)
465:1-8 (1993)), and caged inositol-1,4,5-triphosphate (IP
3
) (see, e.g., Walker, J. W., et al.,
Nature
327:249-252 (1987)).
SUMMARY OF THE INVENTION
In general, the invention features a protecting group derived from a halogenated coumarin group, a quinoline-2-one group, a xanthene group, a thioxanthene group, a selenoxanthene group, or an anthracene group. The protecting group is photolabile and can be removed by irradiating the group with light, such as flash photolysis with ultraviolet radiation or pulsed infrared radiation.
In one aspect, the invention features a protecting group derived from a halogenated coumarin or quinoline-2-one group. The protecting group can be a part of a compound. The compound has the formula:
In the formula: A is —OH, substituted or unsubstituted alkoxy, —OC(O)CH
3
, —NH
2
, or —NHCH
3
; each of X
1
and X
2
, independently, is H, Cl, Br, or I, at least one of X
1
and X
2
being Cl, Br, or I, Q is —O—, —NH—, or —NCH
3
—; Y
1
is —H, —Cl, —Br, —I, —C(O)OH, —NO
2
, —C(O)NHR
1
, —CN, —C(O)H, —C(O)CH
3
, benzoxazol-2-yl, benzothiazol-2-yl, or benzimidazol-2-yl; Y
2
is —H, —C(O)OH, or —SO
3
H; M
1
is —H, —CH
3
, —NR
2
R
3
, —C(O)NR
2
R
3
, or —COOH; Z is a leaving group and M
2
is —H, or Z and M
2
together are ═N
2
, ═O, or ═NNHR
1
; and each of R
1
, R
2
, and R
3
, independently, is a substituted or unsubstituted moiety selected from the group consisting of a C
1-20
alkyl, a C
2-20
alkenyl, a C
2-20
alkynyl, a C
1-20
alkoxy, a C
1-20
thioalkoxy, a C
1-20
alkylsulfonyl, a C
4-16
arylsulfonyl, a C
2-20
heteroalkyl, a C
2-20
heteroalkenyl, a C
3-8
cycloalkyl, a C
3-8
cycloalkenyl, a C
4-16
aryl, a C
4-16
heteroaryl, and a C
2-30
heterocyclyl. The compound can be a salt.
In another aspect, the invention features a protecting group derived from a xanthene group, a thioxanthene group, a selenoxanthene group, or an anthracene group. The protecting group can be a part of a compound. The compound has the formula:
In the formula: E
1
is —OH, substituted or unsubstituted alkoxy, —OC(O)CH
3
, —NH
2
, —NHCH
3
, or —N(CH
3
)
2
; E
2
is ═O, ═NH
2
+
, ═NHCH
3
+
, or ═N(CH
3
)
2
+
; G is O, S, SO
2
, Se, or C(CH
3
)
2
; each of J
1
, J
2
, J
3
, and J
4
, independently, is H, F, Cl, Br, or I; each of L
1
and L
2
, independently, is H, —C(O)OH, or —SO
3
H; M
1
is —H, —CH
3
, substituted amino, disubstituted amino, amido, —COOH, substituted or unsubstituted C
1-20
alkyl, substituted or unsubstituted C
2-20
heteroalkyl, or substituted or unsubstituted C
2-30
heterocyclyl; Z is a leaving group and M
2
is —H, or Z and M
2
together are ═N
2
, ═O, or ═NNHR
1
; and R
1
is a substituted or unsubstituted moiety selected from the group consisting of a C
1-20
alkyl, a C
2-20
alkenyl, a C
2-20
alkynyl, a C
1-20
alkoxy, a C
1-20
thioalkoxy, a C
1-20
alkylsulfonyl, a C
4-16
arylsulfonyl, a C
2-20
heteroalkyl, a C
2-20
heteroalkenyl, a C
3-8
cycloalkyl, a C
3-8
cycloalkenyl, a C
4-16
aryl, a C
4-16
heteroaryl, and a C
2-30
heterocyclyl. The compound can be a salt.
In preferred embodiments, Z and M
2
together are ═N
2
, ═O, or ═NNHR
1
. In other preferred embodiments, Z is a leaving group and M
2
is —H.
A leaving group is a group that can be photolytically displaced. Generally, a leaving group departs from a substrate with the pair of electrons of the covalent bond between the leaving group and the substrate. Preferred leaving groups stabilize the pair of electrons via the presence of electron withdrawing groups, aromaticity, resonance structures, or a combination thereof. Examples of leaving groups include halide, or moieties linked by a carboxylate, a carbonate, an amide, a carbamate, a phosphate, a sulfonate, an amino, an aryloxide, or a thiolate group.
When Z is a leaving group, Z can be a halogen, —OC(O)R
4
, —OP(O)R
5
R
6
, —OP(O)(OH) R
5
, —OC(O)NR
5
R
6
, —NR
5
C(O)OR
6
, —SR
4
, alkoxy, aryloxy, —NR
5
R
5
, —NR
5
C(O)R
6
, —O
3
SR
4
, or —O—NN(O)(NR
5
R
6
). Each of R
4
, R
5
, and R
6
, independently, can be a substituted or unsubstituted moiety selected from the group consisting of a C
1-20
alkyl, a C
2-20
alkenyl, a C
2-20
alkynyl, a C
1-20

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