Synthesis and biological properties of maleimide-based macrocyclic lactone enediynes

Abstract

Natural enediyne antibiotics are powerful DNA-cleavage agents due to the presence of the highly reactive hex-3-ene-1,5-diyne units. However, the complicated chemical structure and thermal instability make their synthesis, derivatization, and storage challenging. Heterocycle-fused enediynes, which exhibit strong antineoplastic activity, are promising analogues of natural enediynes for medicinal applications. To this end, a series of maleimide-based enediynes with macrocyclic lactone moieties were synthesized through the Sonagashira coupling reaction. Differential scanning calorimetry and electron paramagnetic resonance results showed that these macrocyclic enediynes exhibited a rather low onset temperature and the ability to generate radicals at physiological temperature. In addition, the structure–activity relationship of enediynes was analyzed by changing the ring size and the substituents on the propargyl group. Cellular experiments indicated that the diradicals produced by these enediynes efficiently cleaved DNA and disrupted the cell cycle distribution, and consequently induced tumor cell death via an apoptosis pathway at low half inhibitory concentrations. Computational studies suggested that the maleimide moiety promoted the propargyl-allenyl rearrangement of the cyclic enediyne, enabling the generation of diradical species through the Myers–Saito cyclization, and then abstracted hydrogen atoms from the H-donors.