Dna-binding polyamide drug conjugates

Abstract

A conjugate of formula: V—(Y)—Z-T: (I), T-X—B—(Y)—Z-T': (II), V—(Y)Z—(Y′)V′: (III), T-X—B—(Y)—Z—(Y′)—X′—B′-T′: (IV), V—(Y)—Z—(Y′)—X—B-T: (V), V—(Y)—Z—X—B—Z′—(Y′)—(V′): (VI), or (W)—(Y)—[(Z)—(Y′)—(X—B)—(Y″)—(Z′)]—(Y . . . )—(W′): (VII), in which W and W′ are independently a DNA intercalator or terminal subunit, V and V′ are independently a DNA intercalator, X and X′ are independently a DNA alkylator, B and B′ are the same or different and each is a heteoaromatic residue that is attached to the Nterminus of an alkylator subunit (X or X′), Y, Y′, Y″ and Y′″ are independently a linker, T and T′ are independently terminal subunits, Z and Z′ are independently a polyamide group that binds to the minor groove of DNA, a, b, c, d, f, g, i, and j are independently 0 to 5, and e and h are independently 1 to 5, a composition comprising a conjugate of any of formulae (I)-(VII) and a carrier, and a method for treating cancer in a mammal comprising administering an effective amount of a conjugate of any of formulae (I)-(VII) or a composition comprising same.