Bis-anthracyclines with high activity against doxorubicin resistant tumors
First Claim
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1. A compound comprising a first anthracycline analog operatively linked via a linker to a second anthracycline analog through a saccharide unit of the first anthracycline analog to the second anthracycline analog.
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Abstract
The present invention discloses new and novel bisanthracyclines linked through the saccharide portions. These compounds show high activity against two clinically relevant mechanisms of resistance. A novel approach of the invention produces compounds that are as active or more so than the parent compounds. Furthermore, the inventor'"'"'s discovery is also for the design of effective DNA-binding bisanthracyclines as well as anthracyclines mixed with other intercalators and groove binders.
95 Citations
25 Claims
- 1. A compound comprising a first anthracycline analog operatively linked via a linker to a second anthracycline analog through a saccharide unit of the first anthracycline analog to the second anthracycline analog.
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7. A compound having the formula:
- ##STR5## wherein;
R1 is a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3), a fatty acyl group having the general structure --O--CO(CH2)n CH3, wherein n is an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)1 (CH═
CH)m (CH2)n CH3 1 is an integer between 1 to 3, m is an integer between 1 and about 6 and n is an integer between 1 to about 9;each of R2, R3, R9, and R10 is, independently of the others, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a double bonded oxygen moiety; R4 and R11 are, independently of the other, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a halide ion; R5 and R7 are, independently of each other, a saccharide or a molecule resembling a carbohydrate molecule; R6 is a phenyl group, a benzyl group, an aryl group, an alkyl group, a heterocycle, an aromatic heterocycle, a cycloalkane group, a cycloalkyl group, an alkylaryl group, an aryloalky group, an aryl group linked to another aryl group through an ester linkage, an aryl group linked to an alkyl group with an ester linkage, an aryl group linked to another aryl group through an ether linkage, an aryl group linked to an alkyl group through a thiolester linkage, an alkyl group linked to another alkyl group through an ester linkage, an alkyl group linked to another alkyl group through an ether linkage, an alkyl group linked to another alkyl group through an amino group, an aryl group linked to an alkyl through an amino group, an alkyl group linked to another alkyl group through a disulphide group, an aryl group linked to another alkyl group through a disulphide group, an aryl group linked to another aryl group through a disulphide group, an alkyl group linked to another alkyl group through a thioester linkage, an aryl group linked to an alkyl group through a polyester linkage, an aryl group linked to another aryl group through a polyester linkage, an alkyl group linked to another alkyl group through a polyamine linkage, an aryl group linked to an alkyl group through a polyamine linkage, an aryl group linked to another aryl through a polyamine linkage, an alkyl group linked to another alkyl group through a polythioester linkage, an aryl group linked to an alkyl group through a polythioester linkage, or an aryl group linked to another aryl through a polythioester linkage; R8 is a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3), a fatty acyl group having the structure --O--CO(CH2)n CH3, wherein n=an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)1 (CH═
CH)m (CH2)n CH3 where l is an integer between 1 to 3, m is an integer between 1 and 6 and n is an integer between 1-9; andeach of Y1, Y2, Y3, and Y4 is, independently of the others, a hydrogen (--H) group; an hydroxyl group (--OH);
a methoxy group (--OCH3);
or a double bonded oxygen, suphur, or nitrogen group. - View Dependent Claims (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
- ##STR5## wherein;
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24. A method of treating a patient with cancer, comprising administering to a patient a therapeutically effective amount of a bis-anthracycline having a formula:
- ##STR10## wherein;
R1 is a hydrogen (--H) group an hydroxyl group (--OH), a methoxy group (--OCH3), a fatty acyl group having the general structure --O--CO(CH2)n CH3, wherein n is an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)1 (CH═
CH )m (CH2)n CH3 l is an integer between 1 to 3, m is an integer between 1 and about 6 and n is an integer between 1 to about 9;each of R2, R3, R9, and R10 is, independently of the others, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a double bonded oxygen moiety; R4 and R11 are, independently of the other, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a halide ion; R5 and R7 are, independently of each other, a saccharide or a molecule resembling a carbohydrate molecule; R6 is a phenyl group, a benzyl group, an aryl group, an alkyl group, a heterocycle, an aromatic heterocycle, a cycloalkane group, a cycloalkyl group, an alkylaryl group, an aryloalky group, an aryl group linked to another aryl group through an ester linkage, an aryl group linked to an alkyl group with an ester linkage an aryl group linked to another aryl group through an ether linkage, an aryl group linked to an alkyl group through a thiolester linkage, an alkyl group linked to another alkyl group through an ester linkage, an alkyl group linked to another alkyl group through an ether linkage, an alkyl group linked to another alkyl group through an amino group, an aryl group linked to an alkyl through an amino group, an alkyl group linked to another alkyl group through a disulphide group, an aryl group linked to another alkyl group through a disulphide group, an aryl group linked to another aryl group through a disulphide grout, an alkyl group linked to another alkyl group through a thioester linkage, an aryl group linked to an alkyl group through a polyester linkage, an aryl group linked to another aryl group through a polyester linkage, an alkyl group linked to another alkyl group through a polyamine linkage, an aryl group linked to an alkyl group through a polyamine linkage, an aryl group linked to another aryl through a polyamine linkage, an alkyl group linked to another alkyl group through a polythioester linkage, an aryl group linked to an alkyl group through a polythioester linkage, or an aryl group linked to another aryl through a polythioester linkage; R8 is a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3), a fatty acyl group having the structure --O--CO(CH2)n CH3, wherein n=an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)l (CH═
CH)m (CH2)n CH3 where l is an integer between 1 to 3, m is an integer between 1 and 6 and n is an integer between 1-9; andeach of Y1, Y2, Y3, and Y4 is, independently of the others, a hydrogen (--H) group;
an hydroxyl group (--OH);
a methoxy group (--OCH3);
or a double bonded oxygen, sulphur, or nitrogen group.
- ##STR10## wherein;
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25. A therapeutic kit comprising, in suitable container means, a pharmaceutically acceptable composition comprising a bis-anthracycline, having the formula:
- ##STR11## wherein;
R1 is a hydrogen (--H) group an hydroxyl group (--OH), a methoxy group (--OCH3) a fatty acyl group having the general structure --O--CO(CH2)n CH3, wherein n is an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)l (CH═
CH)m (CH2)n CH3 l is an integer between 1 to 3, m is an integer between 1 and about 6 and n is an integer between 1 to about 9;each of R2, R3, R9, and R10 is independently of the others, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a double bonded oxygen moiety; R4 and R11 are, independently of the other, a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3) or a halide ion; R5 and R7 are, independently of each other, a saccharide or a molecule resembling a carbohydrate molecule; R6 is a phenyl group, a benzyl group, an aryl group, an alkyl group, a heterocycle, an aromatic heterocycle, a cycloalkane group, a cycloalkyl group an alkylaryl group, an aryloalky group, an aryl group linked to another aryl group through an ester linkage, an aryl group linked to an alkyl group with an ester linkage, an aryl group linked to another aryl group through an ether linkage, an aryl group linked to an alkyl group through a thiolester linkage, an alkyl group linked to another alkyl group through an ester linkage, an alkyl group linked to another alkyl group through an ether linkage, an alkyl group linked to another alkyl group through an amino group, an aryl group linked to an alkyl through an amino group, an alkyl group linked to another alkyl group through a disulphide group, an aryl group linked to another alkyl group through a disulphide group, an aryl group linked to another aryl group through a disulphide group, an alkyl group linked to another alkyl group through a thioester linkage, an aryl group linked to an alkyl group through a polyester linkage, an aryl group linked to another aryl group through a polyester linkage, an alkyl group linked to another alkyl group through a polyamine linkage, an aryl group linked to an alkyl group through a polyamine linkage, an aryl group linked to another aryl through a polyamine linkage, an alkyl group linked to another alkyl group through a polythioester linkage, an aryl group linked to an alkyl group through a polythioester linkage, or an aryl group linked to another aryl through a polythioester linkage; R8 is a hydrogen (--H) group, an hydroxyl group (--OH), a methoxy group (--OCH3), a fatty acyl group having the structure --O--CO(CH2)n CH3, wherein n=an integer from 1 to about 20, or a fatty acyl group having the general structure --O--CO(CH2)l (CH═
CH)m (CH2)n CH3 where l is an integer between 1 to 3, m is an integer between 1 and 6 and n is an integer between 1-9; andeach of Y1, Y2, Y3, and Y4 is, independently of the others, a hydrogen (--H) group;
an hydroxyl group (--OH);
a methoxy group (--OCH3);
or a double bonded oxygen, sulphur, or nitrogen group.
- ##STR11## wherein;
Specification