Coumarin-linked taxanes for detection and circumvention of cellular efflux

1. A compound comprising:

a structure of Formula 9, salt, stereoisomer, tautomer, polymorph, or solvate thereof;

wherein:

R3, R4, R5, R6, R7, and/or R8 are independently any substituent provided that at least one of R3, R4, R5, R6, R7, and/or R8 is a taxane coupled to a linker, wherein the linker is coupled to Formula 9.

2. The compound of claim 1 , comprising:

a fluorescent taxane derivative having a structure of Formula 1, salt, stereoisomer, tautomer, polymorph, or solvate thereof;

wherein:

L, L-NH, or L-NH—C═O is the linker;

R is selected from:

(a) —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH 2 —R1, —N(R1) 2 or NR1R2, or combination thereof;

(b) —C(O)R1a, —C(O)CH(NR1bR1c)R1a, —C(O)CH(N(R1c)C(O)R1b)R1a, —C(O)CH(N(R1c)C(O)OR1b)R1a, —C(O)CH(N(R1c)C(O)NR1bR1d)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —P(O)(OR1a)R1d, —CH2P(O)(OR1a)R1d, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;

(c) C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 polyaryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, heteroaryl, heterocyclyl, hydrogen, halo, oxygen anion, hydroxy anion, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, C 2 -C 24 alkylcarbonyl, C 6 -C 20 arylcarbonyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, halocarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 24 alkyl)-substituted carbamoyl, di-(C 1 -C 24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C 1 -C 24 alkyl)-substituted amino, mono- and di-(C 5 -C 20 aryl)-substituted amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24 alkylsulfanyl, arylsulfanyl, C 1 -C 24 alkylsulfinyl, C 5 -C 20 arylsulfinyl, C 1 -C 24 alkylsulfonyl, C 5 -C 20 arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, or phosphino, or combinations thereof; and

(d) combinations thereof;

wherein the R group is optionally substituted by a substituent Q, which substituent Q is defined as R; and

wherein R1, R2, R1a, R1b, R1c, or R1d are each independently as defined for R or independently hydrogen.

3. The compound of claim 2 , wherein the linker is selected from:

C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 20 cycloalkyl, C 5 -C 20 aryl, C 5 -C 20 polyaryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, heteroaryl, heterocyclyl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl, C 2 -C 24 alkylcarbonyl, C 6 -C 20 arylcarbonyl, acyloxy, C 2 -C 24 alkoxycarbonyl, C 6 -C 20 aryloxycarbonyl, halocarbonyl, C 2 -C 24 alkylcarbonato, C 6 -C 20 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 24 alkyl)-substituted carbamoyl, di-(C 1 -C 24 alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, amino, amino acid, essential amino acid, L-amino acid, D-amino acid, non-essential amino acid, glycine, beta-alanine, gamma-aminobutyric acid (GABA), mono- and di-(C 1 -C 24 alkyl)-substituted amino, mono- and di-(C 5 -C 20 aryl)-substituted amino, C 2 -C 24 alkylamido, C 6 -C 20 arylamido, or combinations thereof; or

wherein n is an integer.

4. The compound of claim 3 , wherein the linker is selected from glycine, beta-alanine, gamma-aminobutyric acid (GABA).

5. The compound of claim 3 , wherein the linker is glycine.

6. The compound of claim 3 , wherein:

R is selected from —O − , —OH, —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH 2 —R1, —N(R1) 2 or —NR1R2;

R1 is C 1 -C 24 alkyl; and

R2 is hydrogen or C 1 -C 24 alkyl.

7. The compound of claim 6 , wherein the R1 or alkyl is methyl and R2 is hydrogen.

8. The compound of claim 6 , wherein R is selected from —O − , —OH, —NH-methyl.

9. The compound of claim 6 , wherein the linker is selected from glycine, beta-alanine, gamma-aminobutyric acid (GABA).

10. The compound of claim 4 , wherein the fluorescent taxane derivative is selected from Formula 3, Formula 4, or Formula 5 or salt, stereoisomer, tautomer, polymorph, or solvate thereof:

11. The compound of claim 2 , wherein the fluorescent taxane derivative is selected from Formula 6, Formula 7, or Formula 8 or salt, stereoisomer, tautomer, polymorph, or solvate thereof:

wherein n is an integer.

12. The compound of claim 2 , wherein the taxane is selected from:

13. The compound of claim 12 , wherein the linker is selected from:

wherein n is an integer; and

R is selected from —O − , —OH, —NH 2 , —NH-alkyl, —N(alkyl) 2 , —NH 2 —R1, —N(R1) 2 or —NR1R2;

R1 is C 1 -C 24 alkyl; and

R2 is hydrogen or C 1 -C 24 alkyl.

14. The compound of claim 13 , wherein:

R is selected from —O − , —OH, —NH-methyl;

the linker is selected from glycine, beta-alanine, gamma-aminobutyric acid (GABA).

15. A pharmaceutical composition comprising:

the compound of claim 1 ; and

a pharmaceutically acceptable carrier.

16. A method of treating cancer, comprising:

administering the compound of claim 1 to a subject having cancer.

17. The method of claim 16 , wherein the cancer is Kaposi sarcoma, cervical cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer, prostate cancer, melanoma, esophageal cancer, and/or lung cancer.

18. A method of studying of a microtubule, comprising:

contacting the compound of claim 1 to a microtubule in a cell; and

monitoring a functionality of the microtubule in the cell.

19. The method of claim 18 , further comprising visualizing or detecting the microtubule from fluorescence of the compound attached to the microtubule.

20. A method of studying P-glycoprotein, comprising:

contacting the P-glycoprotein, cell having the P-glycoprotein, with the compound of claim 1 ; and

monitoring efflux or no efflux of one or more substances from a cell having the P-glycoprotein.

21. The method of claim 20 , further comprising visualizing or detecting the efflux or no efflux of the compound from the cell from fluorescence of the compound.