Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith

A method of preparing a compound of Formula I comprising a platinum-containing component and a chromophore-containing component,

• wherein:
• (a) in the platinum-containing component,
• X is halo, OC(O)R9, nitrate or sulfate;
• R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, 3, or 4 or R1 and R2 together can be any of the following groups a-h;
• wherein A is H, —CH3, —OCH3, CF3 or NO2;
• R3 is —N(R26)—;
• wherein R26 is hydrogen or C1-C6alkyl;
• R5 is a direct bond, —NH— or C1-C6alkylene;
• or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
• R7 is hydrogen, methyl, —CH(R17)(R18), —C(O)O—R18, or —OC(O)—R18;
• wherein
• R17 is hydrogen or C1-6 alkyl;
• R18 is hydrogen, C1-6 alkyl, —CH(R19)(R20), phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
• R19 is hydrogen or C1-6 alkyl;
• R20 is hydrogen, C1-6 alkyl;
• R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide;
• R11 is hydrogen, hydroxyl, C1-6 alkyl, —OCH3, —CF3, NO2, —N3, —COOH, —CONH2, —CH═CH2, —C≡CH, —(CH2)1-6—OH, —(CH2)1-6—N3, —(CH2)1-6—COOH, —(CH2)1-6—CH═CH2, —(CH2)1-6—C≡CH, —(CH2)0-1(—OCH2CH2)—OH, —(CH2)0-1(—OCH2CH2)1-6—N3, or —(CH2)0-1(—OCH2CH2)1-6—COOH or R11 contain a reactive group on to which a linker and/or one or more of compound W can be added;
• compound W is one or more amino acids, one or more sugars, polymeric ethers, C1-6alkylene-phenyl—NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof;
• wherein R15 is a peptide;
• and
• Z is independently one or more halo or nitro, or one or more counterions sufficient to balance the charge of the compound;
• and
• (b) in the chromophore-containing component,
• R4 is hydrogen, C1-6 alkyl, or CH2—R12;
• R12 is hydrogen, hydroxyl, C1-6 alkyl, —OCH3, —CF3, NO2, —N3, —COOH, —CONH2, —CH═CH2, —C≡CH, —(CH2)1-6—OH, —(CH2)1-6—N3, —(CH2)1-6—COOH, —(CH2)1-6—CH═CH2, —(CH2)1-6—C≡CH, —(CH2)0-1(—OCH2CH2)—OH, —(CH2)0-1(—OCH2CH2)1-6—N3, or —(CH2)0-1(—OCH2CH2)1-6—COOH, or either or both of R11 and R12 contain a reactive group on to which a linker and/or one or more of compound W can be added;
• R6 is independently an amino, a nitro, —NHC(O)(R10), —NHC(O)O(R10), —C(O)NHR10, —OC(O)NHR10, or halo;
• R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
• q is 0, 1, or 2;
• R8 is —H or -C1-6alkyl;
• E is C1-C6alkylene;
• G and G1 are independently N or CR16;
• R16 is hydrogen or methyl;
• and
• the benzene ring which is T is optionally present;
• comprising reacting a chromophore with a platinum nitrile complex, wherein the chromophore is a precursor of the chromophore-containing component and the platinum nitrile complex is a precursor of the platinum-containing component.