Cell-permeable probes for identification and imaging of sialidases

Patent metadata

Field	Value
Publication number	US-10214765-B2
Application number	US-201815881581-A
Country	US
Kind code	B2
Filing date	Jan 26, 2018
Priority date	Aug 18, 2012
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Provided herein are compounds for use as sialidase inhibitors, including alkynyl-3-fluorosialyl fluoride. The compounds, which include the compound DFSA, function by trapping a 3-fluorosialylenzyme intermediate (reporter-inhibitor-enzyme conjugate). These compounds can be conjugated with a detectable tagging moiety for isolation and identification of sialidases.

First claim

We claim:

1. A compound of formula (I):

or a salt thereof,
wherein
F atom at the C3-position is axial or equatorial;
R 1 is H or C 1-6 alkyl;
R 2 is OR 2O , N 3 , N(R 2N ) 2 , or —NH(C═NH)NH 2 ;
each instance of R 2O is independently hydrogen, C 1-6 alkyl, acyl, or a hydroxyl protecting group;
each instance of R 2N is independently hydrogen, C 1-6 alkyl, acyl, or an amine protecting group;
each instance of R 3a and R 3b is independently hydrogen, —C(═O)—R 3r , or a hydroxyl protecting group;
each instance of R 3r is C 1-6 alkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, or alkylheterocyclyl;
X is selected from the group consisting of —O—, —O(C═O)—, —NH—, —NH(C═O)—, —(C═O)NH—, —O(C═O)NH—, —O(C═S)NH—, —NH(C═O)NH—, and —NH(C═S)NH—;
R 4 is H, C 1-6 alkyl, or -L-Z;
Y is CF 3 , C 1-6 alkyl or -L-Z;
each instance of L is independently selected from the group consisting of —(CH 2 ) n —, —(CH 2 ) n C═O—, —(CH 2 ) n NH—, —(C═O)(CH 2 ) n —, —(CH 2 ) n NH(C═O)—, —(C═O)(CH 2 ) n NH(C═O)—, —(CH 2 ) n SCH 2 (C═O)—, and —(CH 2 CH 2 O) n —;
each instance of n is an integer from 1 to 8, inclusive;
each instance of Z is alkynyl, alkenyl, halogen, N(R N ) 2 , OR O , SR S , or CO 2 R O ;
each instance of R N is independently hydrogen, C 1-6 alkyl, acyl, or an amine protecting group;
each instance of R O is independently hydrogen, C 1-6 alkyl, acyl, or a hydroxyl protecting group;
each instance of R S is independently hydrogen, C 1-6 alkyl, or a thiol protecting group;
provided that the compound is not of the formula

provided that when R 4 is -L-Z, Y is C 1-6 alkyl; and
provided that when Y is -L-Z, R 4 is H or C 1-6 alkyl.

2. The compound of claim 1 of formula (II-a):

or a salt thereof,
wherein R 3c is independently hydrogen, C 1-6 alkyl, acyl, or a hydroxyl protecting group.

3. The compound of claim 2 of formula (II-b):

or a salt thereof.

4. The compound of claim 3 , having a formula (II-b1):

or a salt thereof.

5. The compound of claim 4 , having the formula (II-b2):

wherein R y1 is hydrogen, halogen, or C 1-6 alkyl,
or a salt thereof.

6. The compound of claim 1 of formula (II-c):

or a salt thereof.

7. The compound of claim 6 , having a formula selected from (II-c1) and (II-C2):

wherein R y2 is hydrogen or C 1-6 alkyl,
or a salt thereof.

8. The compound of claim 6 , wherein Y is C 1-6 alkyl.

9. The compound of claim 8 , wherein Y is methyl or CF 3 .

10. The compound of claim 1 , wherein R 1 is H or methyl.

11. The compound of claim 1 , wherein the F atom at the C3-position is axial.

12. The compound of claim 1 , wherein the F atom at the C3-position is equatorial.

13. The compound of claim 1 , wherein R 3a is —C(═O)—R 3r , wherein R 3r is C 1-6 alkyl or aryl.

14. The compound of claim 1 , wherein R 3a is benzoyl.

15. The compound of claim 1 , wherein R 3a is CH 3 CO—, C 2 H 5 CO—, C 3 H 7 CO—, t-BuCO—, CF 3 CO—, PhCH 2 CO—, or C 6 H 5 CO—.

16. The compound of claim 1 , wherein the compound is one of the following formulae:

Assignees

• Academia Sinica

Inventors

• Wong Chi-Huey
• Fang Jim-Min
• Cheng Yih-Shyun E
• Tsai Chamg-Sheng

Classifications

• C12Q1/34 Primary

  involving hydrolase · CPC title

• G01N2333/11

  Orthomyxoviridae, e.g. influenza virus · CPC title

• C12Q1/04

  Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor {(C12Q1/6897 takes precedence)} · CPC title

• C12Y302/01018

  Exo-alpha-sialidase (3.2.1.18), i.e. trans-sialidase · CPC title

• C07H5/00

  Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium · CPC title