DNA-binding polyamide drug conjugates

A conjugate of formula:

• wherein
• V and V′ are the same or different and each is a substituted doxorubicin, a substituted daunorubicin. imidazoacridone. a substituted 3-nitrophthalamide or a substituted 3-aminophthalamide.
• wherein the substituent is selected from the group consisting of C1-12 alkyl, C3-8 cycloalkyl, C6-30 aryl, C5-30 heteroaryl, tolyl, xylyl, mesityl, anisyl, hydroxy, C1-12 alkoxy, phenoxy, benzyloxy, acyloxy, halogen, cyano, benzyl, formyl, phenylcarbonyl, benzylcarbonyl, acetyl, carboxyl, carboxy-C1-12 alkyl, carboxy-C1-12 alkylamido, carboxy-C1-12 dialkylamido, carboxamido, amino, C1-12 alkylamino, C1-12 dialkylamino, C1-12 alkylcarbonyl, C6-30 arylamino, C6-30 diarylamino, mercapto, C1-12 alkylthio, nitro, nitrophenyl, nitrobenzyl, C1-12 trialkylsilyl, sulfonyl, C1-12 trialkylammonium, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl,
• B is a heteroaromatic residue comprising a subunit of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2-carboxylic acid, 4-amino-1methyl-3-hydroxypyrrole-2-carboxylic acid, γ-amino-butyric acid, α,γ-diamino-butyric acid, glutamic acid, 8-amino-3,6-dioxanioic acid, β-alanine, 4-amino-benzoic acid, 3-amino-benzoic acid, 2-aminothiazole-5-carboxylic acid, 4-aminothiophene-2-carboxylic acid, 5- aminobenzthiophene-2-carboxylic acid, 5-aminobenzoxazole-2-carboxylic acid, or 5-aminobenzimidazole-2-carboxylic acid,
• Y and Y′ are the same or different and each is a bifunctional linker comprising a group selected from the group consisting of amino, C1-C12 alkylamino, C1-C12 dialkylamino, cycloalkylamino, piperazinyl, piperidinyl, pyrazinyl, purinyl, pyridazinyl, pyrrolidinyl, oxazolyl, isooxazolyl, quinolinyl, isoquinolinyl, byrimidinyl, morpholinyl, thiazolyl, isothiazolyl, quinoxalinyl, quinazolinyl, pyrrolyl, imidazolyl and an amino acid residue,
• in each repeat unit designated by n or p, Q is independently N or CR2,
• R1 and R2 are the same or different and each is selected from the group consisting of hydrogen, C1-C12 alkyl, hydroxy, and halogen,
• n and p are independently 1 to 6,
• o is 0 or 1, and
• a and b are independently 0 to 1.

A conjugate of formula:

• wherein
• V and V′ are the same or different and each is doxorubicin, daunorubicin, or imidazoacridone,
• B is a heteroaromatic residue comprising a subunit of 2-carbonyl-1H-indole or 2-carbonyl-benzofuran,
• Y and Y′ are the same or different and each is a bifunctional linker comprising a group selected from the group consisting of amino, C1-C12 alkylamino, C1-C12 dialkylamino, cycloalkylamino, piperazinyl, piperidinyl, pyrazinyl, purinyl, pyridazinyl, pyrrolidinyl, oxazolyl, isooxazolyl, quinolinyl, isoquinolinyl, byrimidinyl, morpholinyl, thiazolyl, isothiazolyl, quinoxalinyl, quinazolinyl, pyrrolyl, imidazolyl and an amino acid residue,
• in each repeat unit designated by n or p, Q is independently N or CR2,
• R1 and R2 are the same or different and each is selected from the group consisting of hydrogen, C1-C12 alkyl, hydroxy, and halogen,
• n and p are independently 1 to 6,
• o is 0 or 1, and
• a and b are independently 0 to 1.

A conjugate of formula:

• wherein
• V and V′ are the same or different and each is a substituted doxorubicin, a substituted daunorubicin, or a substituted imidazoacridone, wherein the substituent is selected from the group consisting of C1-12 alkyl, C3-8 cycloalkyl, C6-30 aryl, C5-30 heteroaryl, tolyl, xylyl, mesityl, anisyl, hydroxy, C1-12 alkoxy, phenoxy, benzyloxy, acyloxy, halogen, cyano, benzyl, formyl, phenylcarbonyl, benzylcarbonyl, acetyl, carboxyl, carboxy-C1-12 alkyl, carboxy-C1-12 alkylamido, carboxy-C1-12 dialkylamido, carboxamido, amino, C1-12 alkylamino, C1-12 dialkylamino, C1-12 alkylcarbonyl, C6-30 arylamino, C6-30 diarylamino, mercapto, C1-12 alkylthio, nitro, nitrophenyl, nitrobenzyl, C1-12 trialkylsilyl, sulfonyl, C1-12 trialkylammonium, pyrrolidinyl, dioxanyl, tetrahydrofluranyl, tetrahydropyranyl, piperidinyl, and morpholinyl,
• B is a heteroaromatic residue comprising subunits of 2-carbonyl- 1H-indole or 2-carbonyl-benzofuran,
• Y and Y′ are the same or different and each is a bifunctional linker comprising a group selected from the group consisting of amino, C1-C12 alkylamino, C1-C12 dialkylamino, cycloalkylamino, piperazinyl, piperidinyl, pyrazinyl, purinyl, pyridazinyl, pyrrolidinyl, oxazolyl, isooxazolyl, quinolinyl, isoquinolinyl, byrimidinyl, morpholinyl, thiazolyl, isothiazolyl, quinoxalinyl, quinazolinyl, pyrrolyl, imidazolyl and an amino acid residue,
• in each repeat unit designated by nor p, Q is independently N or CR2,
• R1 and R2 are the same or different and each is selected from the group consisting of hydrogen, C1-C12 alkyl, hydroxy, and halogen,
• n and p are independently 1 to 6,
• o is 0 or 1, and
• a and b are independently 0 to 1.