Bioorthogonal compositions
The present disclosure provides bioorthogonal compositions for delivering agents in a subject. The disclosure also provides methods of producing the compositions, as well as methods of using the same.
1. A functionalized payload of formula
or a pharmaceutically acceptable salt thereof,
wherein
D is a payload;
L is a linker;
R 1 , at each occurrence, is independently alkyl or heteroalkyl,
wherein said alkyl and heteroalkyl are independently substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl.
2. The functionalized payload of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein
the alkyl and heteroalkyl of R 1 are independently substituted with 0, 1, or 2 substituents, each independently selected from the group consisting of ═O hydroxy and —COOH.
3. The functionalized payload of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 at one occurrence is the alkyl; and
R 1 at the second occurrence is the heteroalkyl.
4. The functionalized payload of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl is an alkyl in which one or more of the carbon atoms has been replaced by a heteroatom independently selected from O and N.
5. The functionalized payload of claim 4 , or a pharmaceutically acceptable salt thereof, wherein an oxygen heteroatom in the heteroalkyl is oxidized.
6. The functionalized payload of claim 5 , or a pharmaceutically acceptable salt thereof, wherein the functionalized payload has formula:
7. The functionalized payload of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the alkyl and heteroalkyl are independently substituted with 0 substituents.
8. The functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof, wherein D is an antibiotic agent, antifungal agent, antiviral agent, anticancer agent, cardiovascular agent, CNS agent, anti-inflammatory/anti-arthritic agent, anti-TB/anti-leprosy agent, anti-histaminic/respiratory disorder agent, corticosteroid agent, immunosuppressant agent, or anti-ulcer agent.
9. The functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof, wherein D is selected from at least one of paclitaxel, doxorubicin, daunorubicin, etoposide, irinotecan, SN-38, docetaxel, gemcitabine, podophyllotoxin, carmustine, ixabepilone, patupilone, cyclosporin A, rapamycin, amphotericin, vancomycin, daptomycin, doxycycline, ceftriaxone, trimethoprim, sulfamethoxazole, acyclovir, nystatin, amphotericin B, flucytosine, emtricitabine, gentamicin, colistin, L-dopa, oseltamivir, cefalexin, 5-aminolevulinic acid, cysteine, celecoxib, and nimodipine.
10. The functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof, wherein D comprises a radionuclide.
11. A pharmaceutical formulation comprising the functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A kit comprising:
the functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof;
a support composition comprising a tetrazine-containing group of formula
wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′ R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′ R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S) R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R′″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy;
halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4; and
instructions for use thereof.
13. A method for delivering an effective amount of the functionalized payload of claim 2 to a target location in a subject, the method comprising:
administering to the subject a support composition comprising a tetrazine-containing group of formula
wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′ R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′ R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S) R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R′″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy;
halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4; and
administering to the subject the functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the support composition is hyaluronic acid.
15. A method of treating a cancer, comprising administering to a subject in need thereof
a support composition comprising a tetrazine-containing group of formula
wherein
R 20 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl, CF 3 , CF 2 —R′, NO 2 , OR′, SR′, C(═O)R′, C(═S)R′, OC(═O)R′″, SC(═O)R′″, OC(═S)R′″, SC(═S)R′″, S(═O)R′, S(═O) 2 R′″, S(═O) 2 NR′ R″, C(═O)O—R′, C(═O)S—R′, C(═S)O—R′, C(═S)S—R′, C(═O)NR′R″, C(═S)NR′ R″, NR′R″, NR′C(═O)R″, NR′C(═S)R″, NR′C(═O)OR″, NR′C(═S)OR″, NR′C(═O)SR″, NR′C(═S)SR″, OC(═O)NR′R″, SC(═O)NR′R″, OC(═S) R′R′″, SC(═S)R′R″, NR′C(═O)NR″R″, and NR′C(═S)NR″R″;
R′ and R″ at each occurrence are independently selected from hydrogen, aryl and alkyl;
R′″ at each occurrence is independently selected from aryl and alkyl;
R 30 is halogen, cyano, nitro, hydroxy, alkyl, haloalkyl; alkenyl, alkynyl, alkoxy;
halalkoxy; heteroalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl;
R a , R 31a and R 31b are each independently hydrogen, C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl; and
t is 0, 1, 2, 3, or 4; and
administering to the subject the functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein the support composition is hyaluronic acid.
17. The method of claim 15 , wherein the cancer is a soft tissue sarcoma, melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioblastoma, lung cancer, soft tissue carcinoma, fibrosarcoma, osteosarcoma, or pancreatic cancer.
18. The functionalized payload of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the alkyl and heteroalkyl are independently substituted with 0 substituents.
19. The functionalized payload of claim 4 , or a pharmaceutically acceptable salt thereof, wherein the alkyl and heteroalkyl are independently substituted with 0 substituents.
20. The functionalized payload of claim 5 , or a pharmaceutically acceptable salt thereof, wherein the alkyl and heteroalkyl are independently substituted with 0 substituents.
21. The functionalized payload of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the payload is a therapeutic agent.
22. The functionalized payload of claim 8 , or a pharmaceutically acceptable salt thereof, wherein D is an anticancer agent.
23. The functionalized payload of claim 9 , or a pharmaceutically acceptable salt thereof, wherein D is doxorubicin.