Quinone protected forms and conjugates
The invention provides protected ortho-quinone compounds comprising a group represented by: where —Ar— is optionally substituted phenylene, —X is selected from —NH 2 , —OH and —SH, and the protected forms of each, —W— is optionally substituted methylene, such as methylene, and d is a double or single bond, and the salts and solvates thereof.
1 . A protected ortho-quinone compound comprising a group represented by:
where —Ar— is a phenylene or a substituted phenylene,
—X is selected from —NH 2 , —OH and —SH, and the protected forms of each,
—W— is a methylene or a substituted methylene,
d is a double or single bond, and
the ketol form of the ortho-quinone is selected from the group consisting of β-Lapachone, Rhinacanthone, Dunnione, Biflorin, Tanshinone I, Tanshinone IIA, Tanshinone IIB, Dihydrotanshinone I, Cryptotanshinone, Mansonone A, Mansonone C-G, Miltirone, Salvicine, Caryopteron A, Lantalucratin A-C, pyrroloquinolone quinone and 3-hydroxy-β-lapachone, and the salts and solvates thereof.
2 . The protected ortho-quinone of claim 1 , wherein —X is —NH 2 .
3 . The protected ortho-quinone of claim 1 , wherein —X is the protected form of —OH, and the protecting group is a glycan.
4 . The protected ortho-quinone of claim 3 , wherein the glycan is a monosaccharide.
5 . The protected ortho-quinone of claim 4 , wherein the monosaccharide is glucuronic acid.
6 . The protected ortho-quinone of claim 1 , wherein —Ar— is phenylene.
7 . The protected ortho-quinone of claim 1 , wherein —Ar— is phenylene substituted with one to four substituent groups, with each substituent group independently selected from alkyl, alkoxy, nitro, halo, and amido.
8 . The protected ortho-quinone of claim 1 , wherein —W— is methylene (—CH 2 —).
9 . The protected ortho-quinone of claim 1 , wherein —W— is methylene substituted with one or two groups independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alknyl, C 3-6 cycloalkyl, halogen, C 1-10 haloalkyl, C 1-10 haloalkoxy, C 1-10 aminoalkyl, C 1-10 hydroxyalkyl, C 1-10 azidoalkyl, —NR W1 R W2 , —OR W1 , cyano, carboxy, carbamoyl, sulfamoyl and mercapto, wherein —R W1 and —R W2 are independently selected from hydrogen and C 1-4 alkyl.
10 . The protected ortho-quinone of claim 9 , wherein —W— is methylene substituted with one group selected from C 2-10 alkenyl, C 1-10 alkylamino, C 1-10 alkylhydroxyl, C 1-10 alkylazido and carboxy.
11 . A conjugate of formula:
Z-(L-D) p
where:
—Z is a polypeptide,
-L- is a linker,
p is an integer from 1 to 8,
D is a protected ortho-quinone compound according to claim 1
and the salts and solvates thereof.
12 . The conjugate of claim 11 , wherein -D is connected to -L- via the group —X.
13 . The conjugate of claim 11 , wherein -D is connected to -L- via a substituent to the group —W—, or via a substituent to the group —Ar—.
14 . The conjugate of claim 11 , wherein p is an integer from 1 to 4.
15 . The conjugate of claim 11 , wherein the linker -L- comprises one or more groups that are susceptible to enzymatic cleavage.
16 . The conjugate of claim 11 , wherein the linker -L- is or comprises a group of formula V:
wherein:
-L Q - is a selected from a bond, C 1 -C 10 alkylene and C 1 -C 10 alkylene containing O or NH in the backbone;
-Q X - is an amino-acid residue, a dipeptide, or a tripeptide; and
indicates the position where the group of Formula V is attached to a protected ortho-quinone, -D.
17 . The conjugate of claim 16 , wherein -Q X - is a dipeptide.
18 . The conjugate of claim 16 , wherein -Q X - is selected from the group consisting of:
NH -Phe-Lys- C═O ,
NH Val-Ala- C═O ,
NH Val-Lys- C═O ,
NH Ala-Lys- C═O ,
NH -Val-Cit- C═O ,
NH -Phe-Cit- C═O ,
NH -Leu-Cit- C═O ,
NH -Ile-Cit- C═O ,
NH -Phe-Arg- C═O , and
NH -Trp-Cit- C═O ;
where Cit is citrulline, and NH and C═O are the amino and carboxy terminals of the amino acid residues, which are present as —N(H)— and —C(O)— in the linker of formula V.
19 . The conjugate of claim 11 , wherein the linker -L- is of formula:
-L 1 -S-L 2 -
wherein:
-L 1 - is a polypeptide binding moiety;
-L 2 - is a binding moiety linked to the protected ortho-quinone, D; and
—S— is a spacer.
20 . The conjugate of claim 19 , wherein -L 2 - is a group of formula V:
wherein:
-L Q - is a selected from a bond, C 1 -C 10 alkylene and C 1 -C 10 alkylene containing O or NH in the backbone;
-Q X - is an amino-acid residue, a dipeptide, or a tripeptide; and
indicates the position where the group of Formula V is attached to a protected ortho-quinone, -D.
21 . The conjugate of claim 19 , wherein the spacer, —S—, is or comprises one or more groups selected from C 1 -C 20 alkylene, an alkylenediamine moiety, a (poly)ethylene glycol moiety, an amino acid residue, and combinations thereof.
22 . A method of treating cancer, comprising: administering to a subject a therapeutically-effective amount of a protected ortho-quinone according to claim 1 and the salts and solvates thereof.
23 . The conjugate of claim 11 , wherein the protected ortho-quinone compound is selected from the group consisting of β-Lapachone, Rhinacanthone, Dunnione, Biflorin, Tanshinone I, Tanshinone IIA, Tanshinone IIB, Dihydrotanshinone I, Cryptotanshinone, Mansonone A, C, D, E, F, and G, Miltirone, Salvicine, Caryopteron A, Lantalucratin A, B and C, pyrroloquinolone quinone and 3-hydroxy-β-lapachone.
24 . The method of claim 22 , wherein the protected ortho-quinone compound is selected from the group consisting of β-Lapachone, Rhinacanthone, Dunnione, Biflorin, Tanshinone I, Tanshinone IIA, Tanshinone IIB, Dihydrotanshinone I, Cryptotanshinone, Mansonone A, C, D, E, F, and G, Miltirone, Salvicine, Caryopteron A, Lantalucratin A, B and C, pyrroloquinolone quinone and 3-hydroxy-β-lapachone.