Near-IR light-cleavable conjugates and conjugate precursors
Embodiments of near-infrared light-cleavable heptamethine cyanine-based conjugates, particularly targeting agent-drug conjugates, according to Formula I and conjugate precursors are disclosed. The disclosed targeting agent-drug conjugates are useful for targeted delivery and release of a drug. Methods of making and using the conjugates and precursors also are disclosed.
1. A precursor compound having a structure according to Formula IV, or a salt thereof:
wherein m is 1, 2, 3, 4, or 5;
each n independently is 1, 2, or 3;
R 1 and R 4 independently are alkyl, haloalkyl, cycloalkyl, alkoxy, —ROH, —RC(O)OH, —C(O)—R, or —C(O)—O—R, wherein R is alkyl;
R 2 is C(R c ) 2 wherein each R c independently is H, halo, alkyl, or aryl, or (R 2 ) m collectively is phenyl;
X 1 is O, N, or CH 2 ;
G 1 is
G 2 is
R 6 and R 7 independently are alkyl sulfonate, H, alkyl, alkoxy, or substituted aminoalkyl;
R 8 -R 19 independently are H, alkyl, amino, alkoxy, or alkyl sulfonate;
each Y independently is C(R d ) 2 , S, O, Se, or N(R d ) wherein each R d independently is alkyl or H;
each ring A independently is a 6-membered fused aryl, aliphatic, heteroaliphatic, or heteroaryl ring;
R 28 is hydrogen or a protecting group; and
R 29 is —(CH 2 ) u —C≡CH where u is 1, 2, 3, 4, or 5.
2. The precursor compound of claim 1 , wherein the precursor compound is
wherein R 1 and R 4 are methyl, ethyl, n-propyl, i-propyl, t-butyl, or —(CH 2 ) 2 OH; and
R 6 and R 7 are —(CH 2 ) p SO 3 − or —(CH 2 ) p N(CH 3 ) 3 + , where p is 1, 2, 3, 4, or 5.
3. The precursor compound of claim 1 , wherein R 28 is hydrogen, tert-butyloxycarbonyl, or 9-fluorenylmethyloxycarbonyl.
4. The precursor compound of claim 1 , wherein R 28 is hydrogen.
5. The precursor compound of claim 1 , wherein R 6 and R 7 independently are alkyl sulfonate or substituted aminoalkyl.
6. The precursor compound of claim 1 , wherein R 6 and R 7 independently are —(CH 2 ) p SO 3 − or —(CH 2 ) p N(CH 3 ) 3 − , where p is 1, 2, 3, 4, or 5.
7. The precursor compound of claim 1 , wherein:
R 6 and R 7 are —(CH 2 ) 4 SO 3 − ; or
R 6 and R 7 are —(CH 2 ) 4 N(CH 3 ) 3 + .
8. The precursor compound of claim 1 , wherein R 8 -R 19 are H.
9. The precursor compound of claim 1 , wherein each Y independently is C(CH 3 ) 2 or S.
10. The precursor compound of claim 1 , wherein each Y is C(CH 3 ) 2 .
11. The precursor compound of claim 1 , wherein each ring A is a fused phenyl ring substituted with —SO 3 − .