Prototype systems of theranostic biomarkers for in vivo molecular management of cancer

1. A theranostic system comprising a beacon in combination with or covalently linked to at least one compound selected from the group consisting of:

a quinazoline-based tyrosine kinase inhibitor and

a natural product;

wherein the beacon is a heterometallic compound having a structure as defined by Formula A

wherein R 1a , R 1b and R 1c each independently represent a hydrogen atom or an optionally substituted alkyl or acyl group; Ln 3+ is a trivalent lanthanide metal; TM is a transition metal capable of near infrared emission;

X is a negatively charged counterion;

Z is represented by O, NH, S, a poly(ethylene glycol) linker, a C 1 -C 20 aliphatic chain or a conjugate of a poly(ethylene glycol) linker with a C 1 -C 20 aliphatic chain, wherein the poly(ethylene glycol) linker and the C 1 -C 20 aliphatic chain are conjugated via a peptidic or esteric bond; and

n is 2;

wherein the quinazoline-based tyrosine kinase inhibitor has a structure as defined by Formula I:

wherein R 1 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a , N(R a )(R b ), SR a or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

R 2 represents a hydrogen atom, a halogen atom, OR a , SR a , N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl alkyl group; and

R 3 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a , SR a or N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

wherein R a and R b each independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

and wherein the natural product is a chromanol of the vitamin E superfamily, selected from α-, β-, γ-, and δ-tocopherols, α-, (β-, γ-, and δ-tocotrienols, and monocarboxylic esters of dicarboxylic acids thereof.

2. A theranostic system according to claim 1 , wherein the quinazoline-based tyrosine kinase inhibitor is an anilinoquinazoline-based tyrosine kinase inhibitor having the structure defined by Formula II

wherein each R 1e and R 1f independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl alkyl group;

R 2 represents a hydrogen atom, a halogen atom, OR a , SR a , N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group; and

R 3 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a or N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl alkyl group;

wherein R a and R b each independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group.

3. A theranostic system according to claim 2 , wherein R 1e represents a hydrogen atom and R 1f represents an optionally substituted aryl, aralkyl, heterocyclyl or heterocyclylalkyl group.

4. A theranostic system according to claim 2 wherein R 1f represents

wherein n is 0 to 4, and each R 1g independently represents a hydrogen atom, a halogen, NO 2 , CN, N 3 , or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group.

5. A theranostic system according to claim 2 wherein R 1f represents a 2-methoxyphenyl, 2-bromophenyl, 2-fluorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 3-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3,5,difluorophenyl, 3,5,dichlorophenyl, 3,5,dibromophenyl, 3-(trifluoromethyl)phenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-isopropylphenyl, 3-bromo-5-(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl, 4-(tert-butyl)phenyl or 1-napthylmethyl moiety.

6. A theranostic system according to claim 1 , wherein R 2 represents a hydrogen atom, a halogen atom OR c , N(R c )(R d ), SR c or an optionally substituted alkyl group; wherein Rc and Rd each independently represent a hydrogen atom or an optionally substituted alkyl or acyl group.

7. A theranostic system according to claim 1 , wherein R 3 represents a hydrogen atom, a halogen atom OR g , N(R g )(R h ), SR g or an optionally substituted alkyl, alkenyl or alkynyl group; wherein R g and R h each independently represent a hydrogen atom or an optionally substituted alkyl, acyl, alkenyl or alkynyl group.

8. A theranostic system according to claim 1 , wherein the system comprises a complex of Formula B

wherein:

R 1a , R 1b and R 1c each independently represent a hydrogen atom or an optionally substituted alkyl or acyl group;

Ln 3+ is a trivalent lanthanide metal;

TM is a transition metal capable of near infrared emission;

X is a negatively charged counterion;

Z is represented by O, NH, S, a poly(ethylene glycol) linker, a C 1 -C 20 aliphatic chain or a conjugate of a poly(ethylene glycol) linker with a C 1 -C 20 aliphatic chain, wherein the poly(ethylene glycol) linker and the C 1 -C 20 aliphatic chain are conjugated via a peptidic or esteric bond;

n is 2; and

R 5 is represented by the structure

wherein R 1 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a , N(R a )(R b ), SR a or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group,

R 1e and R 1f independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group,

R 2 represents a hydrogen atom, a halogen atom, OR a , SR a , N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group, and

R 3 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a , SR a or N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group,

wherein R a and R b each independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclyl alkyl group.

9. A theranostic system according to claim 1 , wherein the system comprises a complex of Formula III or Formula IV

wherein each R 1e and R 1f independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

R 2 represents a hydrogen atom, a halogen atom, OR a , SR a , N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group; and

R 3 represents a hydrogen atom, a halogen atom, N 3 , CN, NO 2 , OR a or N(R a )(R b ), or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

wherein R a and R b each independently represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, acyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group;

and L is a linker selected from the group consisting of (i) a poly(ethylene glycol) linker, (ii) a C 1 -C 20 aliphatic chain; and (iii) a conjugate of a poly(ethylene glycol) linker with a C 1 - 20 aliphatic chain, wherein the poly(ethylene glycol) linker and the C 1 -C 20 aliphatic chain are conjugated via a peptidic or esteric bond.

10. A theranostic system according to claim 2 , wherein R 2 represents a hydrogen atom, a halogen atom, OR c , N(R c )(R d ), SR c or an optionally substituted alkyl group; wherein R c and R d each independently represent a hydrogen atom or an optionally substituted alkyl or acyl group.

11. A theranostic system according to claim 2 , wherein R 3 represents a hydrogen atom, a halogen atom OR g , N(R g )(R h ), SR g or an optionally substituted alkyl, alkenyl or alkynyl group; wherein R g and R h each independently represent a hydrogen atom or an optionally substituted alkyl, acyl, alkenyl or alkynyl group.

12. A theranostic system according to claim 1 , comprising said beacon in combination with or complexed to said quinazoline-based tyrosine kinase inhibitor.

13. A theranostic system according to claim 1 , comprising said beacon in combination with or complexed to said natural product.

14. A theranostic system according to claim 1 , comprising said beacon in combination with or complexed to said quinazoline-based tyrosine kinase inhibitor and further comprising said natural product.

15. A theranostic system according to claim 1 , wherein R 2 is selected from the group consisting of —NHC(═O)CH 2 Cl, —SC(═O)CH 2 Cl, —OC(═O)CH 2 Cl, —NHC(═O)CH 2 Br, —SC(═O)CH 2 Br, —OC(═O)CH 2 Br, —NHC(═O)CH 2 F, —SC(═O)CH 2 F, and —OC(═O)CH 2 F.

16. A theranostic system according to claim 1 , wherein R 3 is selected from the group consisting of a hydrogen atom or OR m or NH(R m ), wherein R m is an acroyl, crotonoyl, pentenoyl or pentadienoyl group, or wherein R m is selected from the group consisting of: