Trigger-activatable sugar conjugates for cancer-selective labeling and targeting
View Patent ↗Disclosed are compounds for the selective labeling of cell-surface sugars in cancer cells. The compounds are activatable by triggers specific to cancer cells, and, when metabolized, label a cancer cell surface sugar with an azide chemical group. Facilitated by a click chemistry reaction, combination of the cell surface-expressed azide with a alkynyl-drug conjugate enables efficient targeted drug delivery to cancer cells with reduced toxicity. Also disclosed are compounds for delivering a drug to an azide-bearing cancer cell, and methods of treating cancer using the compounds.
1. A compound represented by formula (XI) or a pharmaceutically acceptable salt thereof:
K-Pol-L 2 -D (XI);
wherein:
K is
Pol is a polyalkylene glycol;
L 2 is a trigger-responsive moiety comprising a disulfide bond; and
D is
wherein the compound comprises a disulfide moiety.
2. The compound of claim 1 wherein Pol is:
wherein n is 0-5000.
3. The compound of claim 1 wherein one end of the disulfide bond is a bond to the sulfur atom of the moiety:
wherein
R 6 is H, tri((C 1 -C 6 )alkyl)silyl, or —C(O)((C 1 -C 6 )alkyl); or
n is 1 or 2.
4. The compound of claim 1 wherein one end of the disulfide bond is a bond via a sulfur atom to the moiety:
wherein R 6 is H, tri((C 1 -C 6 )alkyl)silyl, —C(O)((C 1 -C 6 )alkyl), or —(C 1 -C 6 )alkyl.
5. The compound of claim 1 wherein one end of the disulfide bond is a bond via a sulfur atom to the moiety:
wherein n is 1 or 2.
6. The compound of claim 1 wherein the compound comprises:
wherein n is 0-5000.
7. A pharmaceutical composition, comprising a compound of claim 1 , and a pharmaceutically acceptable excipient or carrier.
8. The pharmaceutical composition of claim 7 wherein the compound is DM1-SS-PEG-DBCO and n is an integer from 1 to 5000.
9. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein the compound inhibits proliferation of breast cancer cells.
10. The method of claim 9 wherein the compound is DM1-SS-PEG-DBCO and n is an integer from 1 to 5000.
11. The compound DM1-MAL-PEG-DBCO:
wherein n is an integer from 1 to 5000.
12. The compound of claim 11 wherein n is an integer from 4 to 30.
13. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable excipient or carrier.
14. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 11 , wherein the compound inhibits proliferation of breast cancer cells.
15. The compound DM1-SS-PEG-DBCO:
wherein n is an integer from 1 to 5000.
16. The compound of claim 15 wherein n is an integer from 4 to 30.