Synthesis and preliminary biological evaluations of CC-1065 analogues: Effects of different linkers and terminal amides on biological activity

CC-1065 analogues possessing a biologically active CBI functional group and amide-substituted indole and benzofuran were synthesized. The IC50 values of compounds 26, bearing two indoles, and 25, bearing only one indole, are 0.4 and 3 nM, respectively, against U937 leukemia cells in vitro. The IC50 values of compounds 28, bearing a butyramino group, and 27, bearing an acet amino group, are 0.008 and 0.4 nM, respectively, against U937 leukemia cell s in vitro. Compound 29, bearing a double-bond linker, is about 4-fold more potent than 25, bearing no double-bond linker. Compound 26 is highly poten t against all cell lines tested in the NCI in vitro screening with IC50 val ues in the 0.1-5 nM range for most cell lines. Compounds 26 and 30 are high ly active against L1210 leukemia in mice. Compound 26 is also active agains t B16BL6 melanoma in mice. Most importantly, 26 and 30 are not myelosuppres sive at therapeutically effective doses. The mechanism of tumor cell death is through induction of apoptosis, and is accompanied by DNA fragmentation.