Methods and compositions for the manufacture of C-3′ and C-4′ anthracycline antibiotics

1. A substituted anthracycline of the formula:

wherein, R 1 is an alkyl chain, a (—COCH 2 R 13 ) group, or a (C(OH)—CH 2 R 13 )group;

wherein, R 13 is a hydrogen (—H) group, a hydroxyl group (—OH), a methoxy group (—OCH 3 ), an alkoxy group comprising 1–20 carbon atoms, an alkyl group comprising 1–20 carbon atoms, an aryl group comprising 1–20 carbon atoms, a fatty acyl group comprising the general structure —O—CO(CH 2 ) n CH 3 , wherein n=an integer from 1 to about 20, a fatty acyl group comprising the general structure —O—CO(CH 2 ) l (CH═CH) m (CH 2 ) n CH 3 , wherein l is an integer between 1 to 3, m is an integer between 1 and 6, and n is an integer between 1 and 9, a —OCO—(CH 2 ) n —CH 2 NH 2 , group, or a —OCO—(CH 2 ) n —CO 2 H group;

wherein R 2 and R 3 are, independently of the other, a hydrogen (—H), a hydroxyl group (—OH), or a methoxy group (—OCH 3 );

R 4 is a hydrogen (—H) group, a methoxy group (—OCH 3 ), a hydroxyl group (—OH), or a halide;

wherein Y 1 and Y 2 are, independently of the other, a double bonded oxygen, sulphur, or nitrogen atom;

wherein Z is a —H, —OH, a —CO 2 H, or a —CO 2 R group;

wherein R 7 , R 8 , are, independently, —H, —OH, a halide, —OR 19 , —SH, —SR 19 , —NH 2 , —NHR 19 , —N(R 19 ) 2 , or —CH 3 , and R 7 can additionally be a saccharide, wherein R 19 is an alkyl chain, an alkylating moiety, a cycloalkyl chain, a cyclic ring, or a hydrogen;

wherein R 9 is an —H, —CH 3 , alkyl, aryl, CH 2 OH, or, a CH 2 F group;

wherein R 10 , R 11 and R 12 are, independently, —H, —OH, a halide, —OR, —SH, —SR, —NH 2 , —NHR, —N(R) 2 , or a —CH 3 ;

wherein one of R 5 and R 6 is an —H;

wherein one of R 5 and R 6 is a X-alkyl-aromatic-ring (—XAAR) substituent wherein, A is an alkyl group and wherein, AR is an substituted phenyl ring, a substituted five-member ring, a heteroatomic five-member ring, or a heteroatomic six-member ring, of the form:

wherein at least one of R 14 –R 18 is an a (—H) group and wherein at least one of R 14 –R 18 is a hydroxyl group (—OH), a methoxy group (—OCH 3 ), a nitro group (—NO 2 ), an amine group (—NH 2 ), a halide, an alkoxy group comprising 1–20 carbon atoms, an alkyl group comprising 1–20 carbon atoms, an aryl group comprising 1–20 carbon atoms, an alkyl-amino group, an alkyl-thio group, a cyano group (CN, SCN), a —CO 2 H group, or a —CO 2 R group; and

X is a —O, —N, —S, —SO, or a —SO 2 group; and

A is (CH 2 ) n where n=0–10;

wherein, if R 5 is a XAAR substituent R 6 is not and if R 6 is a XAAR substituent R 5 is not.

2. A substituted anthracycline of the formula:

wherein, R 1 is an alkyl chain, a (—COCH 2 R 13 ) group, or a (C(OH)—CH 2 R 13 ) group;

wherein, R 13 is a hydrogen (—H) groups a hydroxyl group (—OH), a methoxy group (—OCH 3 ), an alkoxy group comprising 1–20 carbon atoms, an alkyl group comprising 1–20 carbon atoms, an aryl group comprising 1–20 carbon atoms, a fatty acyl group comprising the general structure —O—CO(CH 2 ) n CH 3 , wherein n=an integer from 1 to about 20, a fatty acyl group comprising the general structure —O—CO(CH 2 ) l (CH═CH) m (CH 2 ) n CH 3 , wherein l is an integer between 1 to 3, m is an integer between 1 and 6, and n is an integer between 1 and 9, a —OCO—(CH 2 ) n —CH 2 NH 2 group or a —OCO—(CH 2 ) n —CO 2 H group;

wherein R 2 and R 3 are, independently of the other, a hydrogen (—H), a hydroxyl group (—OH), or a methoxy group (—OCH 3 );

wherein R 4 is a hydrogen (—H) group, a methoxy group (—OCH 3 ), a hydroxyl group (—OH), or a halide;

wherein Y 1 and Y 2 are, independently of the other, a double bonded oxygen, sulphur, or nitrogen atom;

wherein Z is a —H, —OH, a —CO 2 H, or a —CO 2 R group;

wherein R 5 and R 6 , are, independently, —H, —OH, a halide, —OR 19 , —SH, —SR 19 , —NH 2 , —NHR 19 , —N(R 19 ) 2 or —CH 3 , and R 5 can additionally be an alkylating moiety, wherein R 19 is an alkyl chain, an alkylating moiety, a cycloalkyl chain, a cyclic ring, a hydrogen;

wherein R 9 is an —H, —CH 3 , alkyl, aryl, CH 2 OH, or CH 2 F group;

wherein R 10 , R 11 , and R 12 are, independently, —H, —OH, a halide, —OR, —SH, —SR, —NH 2 , —NHR, —N(R) 2 or —CH 3 ;

wherein one of R 7 and R 8 is an —H and wherein one of R 7 and R 8 is a X-alkyl aromatic-ring (—XAAR) substituent, wherein, A is an alkyl group and wherein, AR is an unsubstituted phenyl ring, a substituted phenyl ring, a substituted five-member ring or a heteroatomic five-member ring, of the general form;

wherein, R 14 —R 18 are independently a (—H) group, a hydroxyl group (—OH), a methoxy group (—OCH 3 ), a nitro group (—NO 2 ), an amine group (—NH 2 ), a halide, an alkoxy group having 1–20 carbon atoms, an alkyl group having 1–20 carbon atoms, an aryl group having 1–20 carbon atoms, an alkyl-amino group, an alkyl-thio group, a cyano group (CN, SCN), an —CO 2 H group, or a —CO 2 R group; and

X is a —O, —N, —S, —SO, or a —SO 2 group; and

A is (CH 2 ) n , where n=0–10;

wherein if R 7 is a XAAR substituent R 8 is not and if R 8 is a XAAR substituent R 7 is not.

3. The substituted anthracycline of claim 1 , wherein the aromatic ring of the —XAAR substituent is disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted.

4. The substituted anthracycline of claim 1 , wherein the substituted anthracycline is formulated into a pharmaceutically acceptable carrier.

5. The substituted anthracycline of claim 2 , wherein the aromatic ring of the —XAAR substituent is disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted.

6. The substituted anthracycline of claim 2 , wherein the substituted anthracycline is formulated into a pharmaceutically acceptable carrier.

7. A method of treating or preventing cancer comprising administering to a patient a substituted anthracycline of claim 1 or claim 2 .

8. The method of claim 7 , wherein the substituted anthracycline is formulated into a pharmaceutically acceptable carrier.

9. The method of claim 7 , wherein the substituted anthracycline is the substituted anthracycline of claim 1 .

10. The method of claim 7 , wherein the substituted anthracycline is the substituted anthracycline of claim 2 .

11. The method of claim 7 , wherein the cancer is breast cancer, lung cancer, ovarian cancer, Hodgkin's disease, non-Hodgkin's lymphoma, acute leukemia, or carcinoma of the testes.

12. The method of claim 11 , wherein the cancer is breast cancer.

13. The substituted anthracycline of claim 1 of the formula: