Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Nandita      Ghosh; Helen   M.   Sheldrake; Mark      Searcey; Klaus      Pors

doi:10.2174/156802609789909812

Abstract

CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products.

Keywords: CC-1065, Duocarmycin SA, adozelesin, CBI, CPI, DNA minor groove binders (MGBs), adenine N3 alkylation, prodrugs