Small molecule dye for molecular imaging and photothermal therapy
Disclosed is a small molecule dye for use in imaging in the near-infrared window, namely between 1000 nm-1700 nm wavelength. The present dyes are also useful for photoacoustic imaging and photothermal therapy. The dyes have a structure of a D-A-D (donor-acceptor-donor) fluorescent compound core and side chains rendering the compounds water soluble and easily conjugated to hydrophilic polymers and/or targeting ligands. Further disclosed is compound, CH1055 that can be PEGylated, conjugated to a targeting ligand, or conjugated to taurine. Key steps utilized to assemble the core structure of the target included a cross-Suzuki coupling reaction, iron reduction and N-thionylaniline induced ring closure. Four carboxylic acid groups were introduced into the donor-acceptor-donor (D-A-D) type fluorescent compound to impart a certain aqueous solubility and to allow facile conjugation to targeting ligands.
1. A method of synthesizing a near-infrared-II fluorophore, comprising:
a) synthesizing a dialkyl 3,3′((arylazanediyl)bis(4,1-phenylene))diacrylate with a reagent of formula Ph 3 PCHCO 2 (alkyl);
b) synthesizing a dialkyl 3,3′((arylazanediyl)bis(4,1-phenylene))propionate from the compound of step a) using hydrogen and a catalyst;
c) halogenating the arylazanediyl group of the compound of step b);
d) protecting two propionate groups of the compound of step c) with a protecting reagent comprising a trimethylsilyl (TMS) group;
e) substituting the halogen of the compound of step d) with a coupling group;
f) reacting a 2,1,3-benzothiodiazole-containing compound with the coupling group of the compound of step e) such that in the resulting compound a 2,1,3-benzothiodiazole-containing group is coupled to two protected dialkyl 3,3′((arylazanediyl)bis(4,1-phenylene))propionate groups;
g) reacting the compound of step f) such that the 2,1,3-benzothiodiazole-containing group of the resulting compound has one more ring than the 2,1,3-benzothiodiazole-containing group of the compound of step f);
h) deprotecting the two protected propionate groups of the compound of step g).
2. The method of claim 1 , wherein the arylazanediyl group is a phenylazanediyl group.
3. The method of claim 1 , further comprising: i) attaching an amino-containing group to the compound of step h) by reacting an amino-containing compound with a propionate group of the compound of step h).
4. The method of claim 3 , wherein the amino-containing compound comprises a sulfonic acid group.
5. The method of claim 4 , wherein the amino-containing compound comprises a taurinyl group.
6. The method of claim 3 , wherein step i) involves hexafluorophosphate benzotriazole tetramethyl uronium (HBTU).
7. The method of claim 3 , wherein the amino-containing compound contains a polyethylene glycolyl group.
8. The method of claim 3 , wherein the amino-containing compound is an affibody.
9. The method of claim 3 , wherein the affibody is an anti-EGFR affibody.
10. The method of claim 1 , wherein step a) involves alkyl (triphenylphosphoranylidene)acetate.
11. The method of claim 1 , wherein the halogenation is bromination.
12. The method of claim 1 , wherein step d) involves N,N′-dicyclohexylcarbodiimide (DCC).
13. The method of claim 1 , wherein the 2,1,3-benzothiodiazole compound has a nitro group at each of the 5 and 6 positions.
14. The method of claim 1 , wherein step f) is a Suzuki coupling.
15. The method of claim 1 , wherein the coupling group is a pinacolboranyl group.
16. The method of claim 1 , wherein step g) involves N-sulfinylaniline (PNSO).