Synthesis and Biological Activity of Unnatural Enediynes

Abstract

Background: The first reports of the natural enediyne anticancer antibiotics date back to the late 1980s; since then, a great deal of interest has been devoted to the chemistry, biology and potential medical applications of this family of compounds. The biological activity of enediynes is linked to the presence of a highly unsaturated hex-1-ene-1,5-diyne system. The thermally induced transformation of this unit into a benzene σ-σ diradical (the Bergman cycloaromatization) is the key step of the antitumor properties of such compounds: 1,4-diaryl radicals are able to abstract H-atoms from the deoxyribose backbone of DNA, thus leading to DNA strand cleavage and ultimately cell death.

Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using focused and high quality papers. Research efforts addressed at understanding and mimicking the various processes involved in the targeting, activation and DNA cleavage associated with these products are described. The potential of a great number of non natural enediynes in the treatment of many infectious diseases, apart their role in anticancer drugs, such as antibacterial activity, protein degradation activity, has been reported Results: Due to the interesting mode of action of this class of compounds, the unique molecular architecture of enediynes has been exploited towards the synthesis of many non natural compounds in order to study and enhance their biological properties. Seventy-six papers were included in this review. It is divided in paragraphs that include: Carbo- oxygen-nitrogen- and sulfur- enediynes, polymers and macrocycles. The synthetic approaches to the different classes of compounds are discussed in detail together with the biological implications of the synthesized compounds Conclusion: The review summarizes the most recent advances in the synthesis and reactivity of non natural enediynes by focusing the attention particularly to the biological properties of the most interesting members of the family of carbo- and hetero- enediynes. The findings of this review confirm the importance of non natural enediynes as potential drugs in the treatment of cancer and many infectious diseases.

Keywords: Antibiotics; DNA cleavage; anticancer; antitumor; bergman cyclization; carbo- and hetero- enediynes.