Natural product inspired design of enediyne prodrugs via rearrangement of an allylic double bond.

Abstract

Cyclodeca-1,5-diyn-3-ene, the parent core of naturally occurring 10-membered ring enediyne antitumor antibiotics, decomposes at 37 degrees C with a t(1/2) value of 18 h. A prodrug approach was envisaged by in situ formation of the core structure via rearrangement of an allylic double bond. Three synthetic methods including intramolecular lithium acetylide addition to aldehyde, intramolecular Nozaki-Hiyama-Kishi reaction, and intramolecular Sonogashira cross-coupling have been established for synthesis of the enediyne precursors, (E)-3-acyloxy-4-(arylmethylidene)cyclodeca-1,5-diynes. The latter are transformed into 10-membered ring enediynes in the presence of a catalytic amount of Ln(fod)(3) under mild reaction conditions. Alternatively, the enediyne precursor dissociates in buffer solution into an allylic cation or a quinone methide intermediate, which reacts with a nucleophile (such as H(2)O) to form the bioactive enediyne. LC-MS data confirmed formation of the 10-membered ring enediyne from the precursor, which exhibits DNA cleavage activity and cytotoxicity against P388 cancer cell line.