Targeted delivery and prodrug designs for platinum-acridine anti-cancer compounds and methods thereof

摘要

Acridine containing cisplatin compounds have been disclosed that show greater efficacy against cancer than other cisplatin compounds. Methods of delivery of those more effective cisplatin compounds to the nucleus in cancer cells is disclosed using one or more amino acids, one or more sugars, one or more polymeric ethers, C1-6alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, epidermal growth factor receptor, antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and/or mixtures thereof; wherein R15 is a peptide.

主权项

1. A compound of Formula I:wherein 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(R6)—; wherein R6 is hydrogen or C1-C6alkyl; R4 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; 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, or —C(O)O—R8; wherein R8 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide; R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide; 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; and if only one of R11 and R12 contains a reactive group, then the other of R11 and R12 is hydrogen; 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; Y is C1-C6alkyl; and Z is one or more counterions sufficient to balance the charge of the compound.