Indolizino [3,2-C] quinoline-based fluorescent probe

Patent metadata

Field	Value
Publication number	US-10787448-B2
Application number	US-201815877872-A
Country	US
Kind code	B2
Filing date	Jan 23, 2018
Priority date	Jul 23, 2015
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

Abstract

Provided is a fluorescent probe composition including an indolizino[3,2-c]quinoline-based compound, and a nucleic acid/protein/cell imaging method using the same. Since the compound of the present invention demonstrates excellent environmental sensitivity, fluorescence intensity, photostability, nucleic acid/protein binding, intracellular permeability, etc., the compound may be effectively used for various studies of protein/cell functions and imaging technologies, such as nucleic acid/protein kinetics, drug-protein interactions, and intracellular protein imaging.

First claim

The invention claimed is:

1. A fluorescent probe composition, comprising an indolizino[3,2-c]quinoline compound represented by Formula 1:

In Formula 1,
R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-12 alkyl, C 1-12 alkoxy group, COOR 8 , substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl,

C 2-12 alkynyl, substituted C 2-12 alkenyl, amine, hydroxyl, aldehyde, nitrile, amide, phenoxy and boronic ester,
R 2 and R 3 are bound with each other to form an aromatic ring, or each independently selected from the group consisting of hydrogen, halogen, C 1-12 alkyl, C 1-12 alkoxy, COOR 8 , substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl,

C 2-12 alkynyl, substituted C 2-12 alkenyl, amine, hydroxyl, aldehyde, nitrile, amide, phenoxy and boronic ester,
R 6 is selected from the group consisting of C 1-12 alkyl, substituted C 2-12 alkenyl,

substituted or unsubstituted C 6-20 aryl, and substituted or unsubstituted C 2-20 heteroaryl,
n is 0, 1, 2 or 3,
R 7 is selected from the group consisting of hydrogen, hydroxyl, halogen and C 1-12 alkyl, and
R 8 is selected from the group consisting of hydrogen, C 1-12 alkyl and C 2-12 alkynyl.

2. The composition of claim 1 , wherein R 1 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-12 alkyl, COOR 8 , and an amine,
R 2 and R 3 are bound with each other to form an aromatic ring, or each independently selected from the group consisting of hydrogen, aldehyde, C 1-12 alkyl, substituted C 2-12 alkenyl, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl and a nitrile,
R 6 is selected from the group consisting of C 1-12 alkyl, substituted C 2-12 alkenyl, substituted or unsubstituted C 6-20 aryl, and substituted or unsubstituted C 2-20 heteroaryl,
n is 0, 1, 2 or 3,
R 7 is selected from the group consisting of hydrogen, hydroxyl, halogen and C 1-6 alkyl, and
R 8 is selected from the group consisting of hydrogen, C 1-12 alkyl and C 2-12 alkynyl.

3. The composition of claim 2 , wherein the substituted C 2-12 alkenyl is linked to a substituent selected from the group consisting of aldehyde, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl, and nitrile.

4. The composition of claim 2 , wherein the substituted C 6-20 aryl and substituted C 2-20 heteroaryl are prepared by linking one to three arbitrary carbon atoms each independently to a substituent selected from the group consisting of hydrogen, amine, hydroxyl, aldehyde, halogen, nitro, C 2-6 alkylester,

CF 3 , COO—, C 1-6 alkyl and C 1-6 alkoxy.

5. The composition of claim 1 , wherein the substituted C 2-12 alkenyl is linked to a substituent selected from the group consisting of aldehyde, substituted or unsubstituted C 6-20 aryl, substituted or unsubstituted C 2-20 heteroaryl, and nitrile.

6. The composition of claim 1 , wherein the substituted C 6-20 aryl and substituted C 2-20 heteroaryl are prepared by linking one to three arbitrary carbon atoms each independently to a substituent selected from the group consisting of hydrogen, amine, hydroxyl, aldehyde, halogen, nitro, C 2-6 alkylester,

CF 3 , COO—, C 1-6 alkyl and C 1-6 alkoxy.

7. The composition of claim 1 , wherein the C 6-20 aryl is selected from the group consisting of phenyl, naphthyl, anthryl and biaryl.

8. The composition of claim 1 , wherein the C 2-20 heteroaryl is selected from the group consisting of pyridyl, pyrimidyl, thiophenyl, pyrrolyl, furanyl, sulforanyl, morpholinyl, and triazolyl.

9. The composition of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, amine and COOR 8 , R 6 is substituted or unsubstituted C 6-20 aryl or substituted or unsubstituted C 2-20 heteroaryl, and R 8 is hydrogen, C 1-12 alkyl or C 2-12 alkynyl.

10. A nucleic acid-, protein- or cell-detecting reagent, comprising the composition of claim 1 .

11. A nucleic acid-, protein- or cell-imaging method using the composition of claim 1 .

12. A fluorescent probe composition, comprising a compound selected from the group consisting of the following compounds:
6-(4-Methoxyphenyl)indolizino[3,2-c]quinoline (Formula 2:IQ 6);
6-(Naphthalen-1-yl)indolizino[3,2-c]quinoline (Formula 3:IQ 9);
Methyl 6-(1H-pyrrol-2-yl)indolizino[3,2-c]quinoline-12-carboxylate (Formula 4:IQ 21);
Ethyl 6-(3-fluorophenyl)indolizino[3,2-c]quinoline-12-carboxylate (Formula 5:IQ 28);
Ethyl 6-(3,4-dimethoxyphenyl)indolizino[3,2-c]quinoline-12-carboxylate (Formula 6:IQ 30);
11-Methyl-6-(p-tolyl)indolizino[3,2-c]quinoline (Formula 7:IQ 15);
6-(Furan-2-yl)-11-methylindolizino[3,2-c]quinoline (Formula 8:IQ 18);
6-(3,5-Dimethoxyphenyl)indolizino[3,2-c]quinoline (Formula 9:IQ 7);
6-(3,4-Dimethoxyphenyl)-11-methylindolizino[3,2-c]quinoline (Formula 10:IQ 17);
6-(3,5-Dimethoxyphenyl)-11-methylindolizino[3,2-c]quinoline (Formula 11:IQ 16);
4-(Indolizino[3,2-c]quinolin-6-yl)-N,N-dimethylaniline (Formula 12:IQ 36);
6-(p-Tolyl)indolizino[3,2-c]quinoline (Formula 13:IQ 3);
11-methyl-6-(thiophen-2-yl)indolizino[3,2-c]quinoline (Formula 14:IQ 52);
6-(5-chlorofuran-2-yl)-11-methylindolizino[3,2-c]quinoline (Formula 15:IQ 53);
12-ethynyl-6-(4-methoxyphenyl)indolizino[3,2-c]quinoline (Formula 16:IQ 55);
4-(5-(indolizino[3,2-c]quinolin-6-yl)-2-methoxybenzyl)morpholine (Formula 17:IQ 56);
ethyl 6-(4-methoxy-3-(morpholinomethyl)phenyl)indolizno[3,2-c]quinoline-12-carboxylate (Formula 18:IQ 57);
2,6-bis(indolizino[3,2-c]quinolin-6-yl)pyridine (Formula 19:IQ 5-D);
6-(4-methoxyphenyl)-5-methylindolizino[3,2-c]quinolin-5-ium methyl sulfate (Formula 20:IQ 6-S1-Me);
5-(2-chloroethyl)-6-(4-methoxyphenyl)indolizino[3,2-c]quinolin-5-ium trifluoromethanesulfonate (Formula 21:IQ 6-S2-Cl);
6-(4-methoxyphenyl)indolizino[3,2-c]quinoline-10-carbonitrile (Formula 22:IQ 67);
6-(4-methoxyphenyl)benzo[7,8]indolizino[3,2-c]quinoline (Formula 23:IQ 77);
6-ethylbenzo[7,8]indolizino[3,2-c]quinoline (Formula 24:IQ 79);
4-(indolizino[3,2-c]quinolin-6-yl)aniline (Formula 25:IQ-B1);
4-(indolizino[3,2-c]quinolin-6-yl)phenol (Formula 26:IQ-B2);
(E)-6-(4-methoxyphenyl)-10-styrylindolizino[3,2-c]quinoline (Formula 27:IQ-B19);
(E)-10-(2-(1H-imidazol-1-yl)vinyl)-6-(4-methoxyphenyl)indolizino[3,2-c]quinoline (Formula 28:IQ-B20);
4-(6-(4-methoxyphenyl)indolizino[3,2-c]quinolin-10-yl)benzaldehyde (Formula 29:IQ-B23);
(E)-3-(6-(4-methoxyphenyl)indolizino[3,2-c]quinolin-10-yl)acrylaldehyde (Formula 30:IQ-B25);
6-(4-methoxyphenyl)indolizino[3,2-c]quinoline-10-carbaldehyde (Formula 31:IQ-B11);
(E)-6-(4-methoxystyryl)indolizino[3,2-c]quinoline (Formula 32:IQ-B12) 6,10-bis(4-methoxyphenyl)indolizino[3,2-c]quinoline (Formula 33:IQ-B26);
(E)-3-(4-(6-(4-methoxyphenyl)indolizino[3,2-c]quinolin-10-yl)phenyl)acrylaldehyde (Formula 34:IQ-B31);
4-(6-(4-methoxyphenyl)indolizino[3,2-c]quinolin-10-yl)-N,N-dimethylaniline

Assignees

• Seoul Nat Univ R&Db Foundation
• Univ Yonsei Iacf

Inventors

• Lee Jeeyeon
• Kim Ikyon
• Kwon Soonbum
• Lim Bumhee

Classifications

• G01N33/582 Primary

  with fluorescent label · CPC title

• G01N21/6486

  Measuring fluorescence of biological material, e.g. DNA, RNA, cells (G01N21/6428 takes precedence) · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C12Q1/6876

  Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes · CPC title