Dynemicin A, Uncialamycin and Analogues

Book Preface

Enediynes are a class of highly cytotoxic natural products mainly produced by actinobacteria and are among the most potent naturally occurring antitumor and antibiotic agents known. The enediyne function, which generally forms the part of a 9- or 10-membered ring, is one of several organic functions that make up these structurally complex, chiral compounds. The limited availability of enediynes through natural product isolation along with their structural complexity, outstanding biological activities and unusual mechanism of action has made this family of molecules a highly attractive synthetic target for both therapeutic applications and more fundamental research [HAM 11].

Neocarzinostatin 1-1 (Figure I.1) was isolated from Streptomyces carzinostaticus as a chromoprotein in 1965, but its structure was not determined until 20 years later. It occurs naturally as a combination of a protein (apoprotein) and the neocarzinostatin chromophore 1-2; the apoprotein ensures the stability of the highly strained 9-membered enediyne motif. The first biological evaluations of 1-1 presented a wide range of antibiotic activity, and excellent inhibitory activity against the proliferation of tumor cells from a large number of cell lines was subsequently shown. 1-1 became the first antitumor protein derivative approved as a drug for clinical use in combination with lipiodol for the treatment of hepatocellular carcinoma in Japan. Its proposed mechanism of action is the induction of apoptosis via radical DNA damage (Scheme I.1) [ISH 65, EDO 85, BAK 07, CHI 11]: chromophore 1-2 is released from chromoprotein 1-1 in the cell and binds to the minor groove of DNA. After a series of reactions initiated by glutathione, a 1,4-benzenoid biradical 1-4 is generated via Myers–Saito cycloaromatization of 1-3 [MYE 89, NAG 89]. This highly reactive biradical