Molecular Design and Chemical Synthesis of Potent Enediynes. 2. Dynemicin Model Systems Equipped with C-3 Triggering Devices and Evidence for Quinone Methide Formation in the Mechanism of Action of Dynemicin A

Continuing the theme of the preceding article, this paper describes the synthesis and chemical properties of designed enediynes related to dynemicin A. These model systems are equipped with triggering devices at C-3 of the aromatic nucleus. The design of these compounds (1 and 2) was based on the hypothesis that a C-3 phenolic group generated in situ would be capable of promoting epoxide opening and subsequent Bergman cycloaromatization according to the dynemicin A cascade. Compound 1 carrying a tert-butyl ester group at C-3 was synthesized from quinoline derivative 28 via the sequence 28 → 36 → 45 → 46 → 47 → 48 → 44 → 49 -→ 50 → 1. Compound 2 carrying the photoremovable (2-nitrobenzyl)oxy group at C-3 was constructed from quinoline 29 by a similar sequence. Exposure of 1 and 49 to aqueous LiOH in EtOH led to Bergman cycloaromatization products 58 and 57, respectively. Compounds 2 and 62 bearing the 2-nitrobenzyl group at C-3 were photolytically converted to free phenolic systems 63 and 64, respectively. Reaction of 63 and 64 with the nucleophiles EtOH, EtSH, or ⁿPrNH₂ under anaerobic conditions in basic buffer solutions led to aromatized products 66-70. Exposure of 63 and 75, on the other hand, with EtOH under aerobic conditions in basic buffer solutions furnished the novel quinone methide epoxide systems 71 and 76-77, respectively. The chemistry of compounds 63 and 64 combined with their DNA-cleaving capabilities provides support for the quinone methide mechanism of action of dynemicin A.