MOLECULAR DESIGN, CHEMICAL SYNTHESIS, AND BIOLOGICAL ACTION OF ENEDIYNES

Over the past few years much of our research has been concerned with an examination of molecules inspired by a new class of antibiotics, the enediynes, which are some of the most potent antitumor agents ever discovered.1 These antibiotics, represented by calcheamicin γ 1 I(l), 2 esperamicin A1 (2), 3 neocarzinostatin chromophore (3), 4 and dynemicin A (4)5 in Chart I, have at their core an unprecedented confluence of acetylenic and olefinic linkages: a structural assembly which lies at the heart of the remarkable activity of these molecules. With the exception of neocarzinostatin chromophore (3), all of these molecules contain a 1, 5- diyn-3-ene unit embedded within a strained 10-membered ring which, upon suitable chemical triggering, is capable of undergoing a cycloaromatization process to generate a benzenoid diradical. It is this diradical which is capable of abstracting hydrogen atoms from the sugar phosphate backbone of DNA, initiating double-stranded DNA cleavage leading to cell death. © 1992, American Chemical Society. All rights reserved.