Synthesis and cytotoxicity of a biotinylated CC-1065 analogue

A biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The IC50 of 6 was 0.7 nM against U937 cells. Compound 6 caused apototsis of U937 cells.For the first time, a biotinalyted CBI-bearing CC-1065 analogue, 6, was synthesized. The biotinylated 6 can serve as a model compound to explore the usefulness of non-radioactive small molecule anticancer drugs in the pretargeting strategy for cancer imaging and therapy.Anticancer drugs generally act on metabolically active or rapidly proliferating cells, and cannot distinguish between cancer and normal cells; thus, toxicities to normal cells limit the dose of drugs that can be given to patients. Therefore, much research has focused on development of more specific therapeutic strategies to reduce toxicity to normal cells. One of these strategies is monoclonal antibody-directed pretargeting technology. The use of pretargeting technology for cancer imaging and treatment has made significant progress in the last few years [1-6]. This approach takes advantage of the fact that biotin binds strongly to proteins avidin and streptavidin [7,8]. Thus, a non-toxic tumor cell specific antibody is conjugated with avidin/streptavidin, and is administered to patients. After the antibody binds to tumor cells (usually 24–48 h); a clearing agent is given to remove the residual circulating antibodies in blood. Lastly, a toxic biotin-radioisotope conjugate is administered. Due to the small size of the biotin-radioisotope molecule and tight binding between biotin and avidin/streptavidin, the biotin-radioisotope rapidly binds to tumor cells with high specificity. This approach decouples the lengthy antibody to target process and the administration of a toxic moiety, but takes full advantage of both the high target specificity of the antibody and the favorable pharmacokinetics of a small toxic molecule. While progress using radioisotopes in this approach has been achieved, few reports on using a potent non-radioactive small molecule antica