Exploring the Chemistry and Biology of Antitumor Enediyne Chromoprotein C-1027

C-1027 is an extremely potent antitumor agent, and belongs to a family of chromoprotein antitumor antibiotics, which contain a carrier apoprotein and highly unstable enediyne chromophore. The enediyne spontaneously aromatizes to generate p-benzyne biradical, and subsequently abstracts hydrogens from the DNA sugar backbone, resulting in the sequence-selective double-strand cleavage. On the other hand, the C-1027 apoprotein functions as a carrier, and is likely to escort the reactive chromophore through the cells until reaching the target DNA. The excitement surrounding this molecule lies in the complex molecular architecture of the chromophore, the important biological activity, and the fascinating mode of action. In this account, our studies in the chemistry and biology of C-1027 are presented in three parts: (1) synthetic study of the C-1027 chromophore, (2) spin-trapping study of the C-1027-induced DNA cleavage, and (3) rational design of a kinetically stabilized analog of C-1027.