Triggering the Antitumor Activity of Acyclic Enediyne through Maleimide-Assisted Rearrangement and Cycloaromatization

Abstract

Acyclic enediynes are generally inactive under physiological conditions to be used as antitumor agents like their natural enediyne counterparts. A new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) is uncovered to trigger the reactivity of acyclic enediynes. Through this mechanism, cascade 1,3-proton transfer processes are accelerated with the maleimide moiety at the ene position to enable the acyclic enediynes to undergo cycloaromatization and generate reactive radicals under physiological conditions. Computational studies suggest that the highest energy barrier for MARACA is 26.0 kcal/mol, much lower than that of Bergman cyclization pathway (39.6 kcal/mol). Experimental results show that maleimide-based enediynes exhibit low onset temperature, fast generation of radical species at 37 °C, and much faster reaction in aqueous solution than in nonpolar solvent, which is beneficial to achieve both high reactivity in physiological environment and high stability for storage and delivery in nonpolar media. The generated radical species are capable of causing high percentage of double-strand (ds) DNA cleavage, leading to significant cytotoxicity toward a panel of cancer cell lines with half inhibition concentration down to submicromolar level. Overall, the discovery of the MARACA mechanism provides a platform for designing novel acyclic enediynes with high potency for antitumor applications.

Experimental and Computational Study on the Reaction Pathways of Diradical Intermediates Formed from Myers‐Saito Cyclization of Maleimide‐Based Enediynes

“…[12] Recently, we uncovered a new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) to trigger the antitumor activity of acyclic enediynes through the facilitated tautomerization of enediyne to enyne-allene and the generation of radical species under physiological conditions. [13] We also found that the phenyl radical formed from MSC could underwent 5-endo ring closure to form a stable product, suggesting the presence of different pathways of the diradical intermediates beside hydrogen-abstracting reactions. Along the same line, we designed enediyne 1 with acid-labile protecting groups which could be converted to enyne-allene 2 and 3 in the present of trifluoroacetic acid (TFA) at 0°C (Scheme 1).…”

“…The reactants were chosen to be AI and BI in Figure 2 (similar to compound 2 and 3 albeit with the benzyl group at the maleimide moiety being replaced with methyl group to reduce calculation burden). The previous reports from our group and other groups had demonstrated that such a computational setup was suitable for enediyne systems [8f,13–14,20] . Unrestricted DFT method together with broken symmetry ansatz was employed in the structure optimizations of transition states in MSC and the resulted diradical products.…”

“…Our group has been dedicated to design and study maleimide‐based enediynes for antitumor applications [12] . Recently, we uncovered a new mechanism named as maleimide‐assisted rearrangement and cycloaromatization (MARACA) to trigger the antitumor activity of acyclic enediynes through the facilitated tautomerization of enediyne to enyne‐allene and the generation of radical species under physiological conditions [13] . We also found that the phenyl radical formed from MSC could underwent 5‐endo ring closure to form a stable product, suggesting the presence of different pathways of the diradical intermediates beside hydrogen‐abstracting reactions.…”

Discotic material hexakis(4‐carboxyphenylethynyl)benzene inhibits Escherichia coli growth via the glycolysis pathway

“…Compound 3 has two phenylethynyl groups at the ortho positions of benzene. It is known that an enediyne moiety is capable of inducing Bergman‐type cyclization, 21,22 causing irreversible double‐stranded DNA scission, when the distance between two triple bonds is smaller than 3.4 Å. However, compound 3 , with a diyne structure, did not significantly inhibit E. coli growth; neither did compound 4 , with two phenylethynyl groups at the para positions, nor compound 5 , with no central benzene ring, significantly inhibited E. coli growth at all.…”

Nucleophilic Addition to Diradicals Derived From Cycloaromatization of Maleimide‐Based Enediynes

“…[27] Following this line, a new mechanism named as maleimide-assisted rearrangement and cycloaromatization (MARACA) to trigger the antitumor potency of enediynes was proposed recently. [28] Moreover, the interception pathways by intramolecular hydrogen atom transfer (HAT) with regard to highly reactive diradicals generated through MARACA have been uncovered, [29] which clearly indicated that the intramolecular HAT pathways to consume the diradical species have posed a challenge to further boost their biological activity unless the enediyne molecules are elaborately designed. On the other hand, because of the involvement of the essential MSC step in the MARACA mechanism, the dual reactivity of the intermediates from cycloaromatization is expected to show up.…”